Methods of treating intraocular pressure with activators of tie-2

ABSTRACT

Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for eye conditions associated with angiogenesis, for example, intraocular pressure, ocular hypertension, and glaucoma.

CROSS REFERENCE

This Application claims the benefit of U.S. Provisional Application No.62/222,481 filed Sep. 23, 2015, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Intraocular pressure is a significant pathology associated withglaucomas, such as primary open angle glaucoma. The intraocular pressureis generated through damage to the trabechular meshwork of the eye,which results in optic nerve damage and loss of vision. Ocularhypertension occurs when the pressure in the eye surpasses the normalrange with no detectable changes in vision or damage to the structure ofyour eyes. People with ocular hypertension have an increased risk ofglaucoma.

INCORPORATION BY REFERENCE

Each patent, publication, and non-patent literature cited in theapplication is hereby incorporated by reference in its entirety as ifeach was incorporated by reference individually.

SUMMARY OF THE INVENTION

In some embodiments, the invention provides a method for reducingintraocular pressure in a subject in need thereof, the method comprisingadministering to the subject a therapeutically-effective amount of aTie-2 activator, wherein the administration reduces the intraocularpressure by about 0.1 mmHg to about 9 mmHg compared to absence ofadministration.

In some embodiments, the invention provides a method for treatingglaucoma in a subject in need thereof, the method comprisingadministering to the subject a therapeutically-effective amount of aTie-2 activator, wherein the administration reduces intraocular pressureby about 0.1 mmHg to about 9 mmHg compared to absence of administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates changes in intraocular pressure from baseline. A:study eye; B: fellow eye.

FIG. 2 illustrates changes in intraocular pressure from baseline. A:Compound 1+ Sham; B: Compound 1+RBZ; C: Placebo+RBA; D: All Compound 1.

FIG. 3 illustrates changes in average plasma concentration of Compound 1after topical ocular administration in male New Zealand White rabbits.

FIG. 4 illustrates changes in average plasma concentration of Compound 1after subcutaneous administration in male New Zealand White rabbits. A:Compound 1 sodium salt; B: Compound 1 free acid.

FIG. 5 illustrates changes in average plasma concentration of Compound 1after intravitreal administration in male New Zealand White rabbits. A:Compound 1 sodium salt; B: Compound 1 free acid.

FIG. 6 illustrates changes in average aqueous humor concentrations aftertopical ocular administration of Compound 1 in male New Zealand Whiterabbits.

FIG. 7 illustrates changes in average aqueous humor concentrations aftersubcutaneous administration of Compound 1 in male New Zealand Whiterabbits. A: Compound 1 sodium salt; B: Compound 1 free acid.

FIG. 8 illustrates changes in average aqueous humor concentrations afterintravitreal administration of Compound 1 in male New Zealand Whiterabbits. A: Compound 1 sodium salt; B: Compound 1 free acid.

FIG. 9 illustrates average vitreous humor concentrations after topicalocular administration of Compound 1 in male New Zealand White rabbits.

FIG. 10 illustrates average vitreous humor concentrations aftersubcutaneous administration of Compound 1 in male New Zealand Whiterabbits. A: Compound 1 sodium salt; B: Compound 1 free acid.

FIG. 11 illustrates average vitreous humor concentrations afterintravitreal administration of Compound 1 in male New Zealand Whiterabbits. A: Compound 1 sodium salt; B: Compound 1 free acid.

FIG. 12 illustrates average iris, retina, choroid, and cornea tissueconcentrations after topical ocular administration of Compound 1 in maleNew Zealand White rabbits at 1.2 mg/eye (˜0.7 mg/kg/dose). A: Iris; B:Retina; C: Choroid; D: Cornea.

FIG. 13 illustrates individual and average iris, retina, choroid, andcornea tissue concentrations after subcutaneous administration ofCompound 1 in male New Zealand White rabbits. A: Iris; B: Retina; C:Choroid; D: Cornea.

FIG. 14 illustrates individual and average iris, retina, choroid, andcornea tissue concentrations after subcutaneous administration ofCompound 1 in male New Zealand White rabbits. A: Iris; B: Retina; C:Choroid; D: Cornea.

FIG. 15 illustrates average iris, retina, choroid, and cornea tissueconcentrations after intravitreal administration of Compound 1 in maleNew Zealand White rabbits. A: Iris; B: Retina; C: Choroid; D: Cornea.

FIG. 16 illustrates average iris, retina, choroid, and cornea tissueconcentrations after intravitreal administration of Compound 1 in maleNew Zealand White rabbits. A: Iris; B: Retina; C: Choroid; D: Cornea.

FIG. 17 illustrates the raw data intraocular pressure (IOP) valuesrecorded after AM dosing of Compound 1 in New Zealand White rabbits over8 days.

FIG. 18 illustrates intraocular pressure (IOP) differences from avehicle control group after AM dosing of Compound 1 in New Zealand Whiterabbits over 8 days.

FIG. 19 illustrates the raw data intraocular pressure (IOP) valuesrecorded after AM dosing of Compound 1 in New Zealand White rabbits onDay 7.

FIG. 20 illustrates intraocular pressure (IOP) differences from avehicle control group after AM dosing of Compound 1 in New Zealand Whiterabbits on Day 7.

FIG. 21 illustrates the raw data intraocular pressure (IOP) valuesrecorded after AM dosing of Compound 1 in New Zealand White rabbits onDay 8.

FIG. 22 illustrates intraocular pressure (IOP) differences from avehicle control group after AM dosing of Compound 1 in New Zealand Whiterabbits on Day 8.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are therapies using a Tie-2 activator for treatment ofelevated intraocular pressure and ocular hypertension. A Tie-2 activatorof the disclosure can activate Tie-2 signaling by promoting proteinphosphorylation, such as phosphorylation of the Tie-2 protein. Theintraocular pressure can be associated with glaucoma.

Tie-2 (tyrosine kinase with immunoglobulin and epidermal growth factorhomology domains 2) is a membrane receptor tyrosine kinase expressedprimarily in vascular endothelial cells and a subset of hematopoieticstem cells (HSCs) and macrophages. The principle regulators of Tie-2phosphorylation are angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2).Ang-1 is an agonist of Tie-2, and binding of Ang-1 to Tie-2 promotesreceptor phosphorylation. Ang-2 is a Tie-2 ligand that acts in acontext-dependent antagonistic or agonistic manner. Binding of Ang-1 toTie-2 increases the level of endogenous Tie-2 receptor phosphorylationand initiates downstream AKT signaling. This binding initiates asignaling cascade that can induce distinctive vascular remodelingthrough highly organized angiogenesis and tightening of the endothelialcell junctions (endothelium cell proximity). Within the vascularendothelium, Ang-1-Tie-2 signaling promotes endothelial cell proximity.In the HSC microenvironment, Ang-1-Tie-2 signaling contributes in aparacrine manner to the long-term repopulation of HSCs.

Under physiological conditions, the duration of Tie-2 phosphorylation isregulated by the human protein tyrosine phosphatase beta (oftenabbreviated as HPTβ or HPTP beta), which removes the phosphate from theTie-2 receptor. By inhibiting HPTβ, the level of Tie-2 phosphorylationsubstantially increases, restoring proper cell proximity. HPTβ plays afunctional role in endothelial cell proliferation, viability,differentiation, vasculogenesis, and angiogenesis. HPTβ and vascularendothelial protein tyrosine phosphatase (VE-PTP; the mouse orthologueof HPTPβ) are expressed in vascular endothelial cells throughoutdevelopment. A small molecule of the disclosure can activate Tie-2downstream signaling by inhibiting HPTPβ/VE-PTP.

A therapy of the disclosure can be used to treat elevated intraocularpressure (IOP). Intraocular pressure arises from increased fluidpressure inside the eye. Pressure within the eye is maintained by thebalance between the fluid entering the eye through the ciliary body andthe fluid exiting the eye through the trabecular meshwork. The normalrange of introcular pressure is between about 10 mmHg to about 21 mmHg.Elevated intraocular pressure in the absence of glaucoma is referred toas ocular hypertension (OHT), which can damage to the trabechularmeshwork that is associated with glaucoma. High pressure in the eye cancause damage to the optic nerve and impair central and peripheralvision.

Failure to diagnose or treat symptoms of IOP, OHT, or glaucoma can leadto permanent vision loss. The glaucoma can be, for example, primaryglaucoma, pseudoexfoliative glaucoma, pigmentary glaucoma, primaryjuvenile glaucoma, open angle glaucoma, wide-angle glaucoma, close-angleglaucoma, congenital glaucoma, acquired glaucoma, secondary glaucoma,inflammatory glaucoma, phacogenic glaucoma, or neovascular glaucoma. Insome cases, a Tie-2 activator of the disclosure can stabilizevasculature associated with the trabechular meshwork, reducingintraocular pressure and treating ocular hypertension.

Tie-2 Activators.

Compounds disclosed herein can be effective as Tie-2 activators. Thecompounds can promote that activity, for example, by binding to orinhibiting HPTPβ. Such compounds can bind to HPTPβ, for example, bymimicking the binding mechanism of a native substrate, such as aphosphorylated compound. A compound can be a phosphate mimetic orbioisostere, for example, a sulfamic acid. The compound could also bederived from an amino acid building block or comprise an amino acidbackbone for efficiency and economy of synthesis.

In some embodiments, a compound of the invention is a compound of theformula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; and Y is H, aryl,heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any ofwhich is substituted or unsubstituted, or

wherein: L is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L is bound forms an amide linkage, a carbamate linkage, or asulfonamide linkage, or a chemical bond, or together with any of R^(a),R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L, R^(b),R^(c), and R^(d) forms a ring that is substituted or unsubstituted;R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or together with any of L, R^(a), R^(c),and R^(d) forms a ring that is substituted or unsubstituted; R^(c) is Hor alkyl which is substituted or unsubstituted, or together with any ofL, R^(a), R^(b), and R^(d) forms a ring that is substituted orunsubstituted; R^(d) is H or alkyl which is substituted orunsubstituted, or together with any of L, R^(a), R^(b), and R^(c) formsa ring that is substituted or unsubstituted; and R^(g) is H, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, or a pharmaceutically-acceptable salt, tautomer, orzwitterion thereof.

In some embodiments, aryl¹ is substituted or unsubstituted phenyl, aryl²is substituted or unsubstituted heteroaryl, and X is alkylene. In someembodiments, aryl¹ is substituted phenyl, aryl² is substitutedheteroaryl, and X is methylene.

In some embodiments, a compound is of the formula:

wherein aryl¹ is para-substituted phenyl, aryl² is substitutedheteroaryl; X is methylene; L is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L is bound forms an amide linkage, a carbamatelinkage, or a sulfonamide linkage, or a chemical bond; R^(a) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; R^(c) isH or alkyl which is substituted or unsubstituted; and R^(d) is H oralkyl which is substituted or unsubstituted.

In some embodiments, aryl¹ is para-substituted phenyl; aryl² is asubstituted thiazole moiety; X is methylene; L together with thenitrogen atom to which L is bound forms a carbamate linkage; R^(a) isalkyl, which is substituted or unsubstituted; R^(b) is arylalkyl, whichis substituted or unsubstituted; R^(c) is H; and R^(d) is H.

In some embodiments, Aryl² is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a thioether group, a thioester group, athioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted; and R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,alkynyl, an alkoxy group, an ether group, a carboxylic acid group, acarboxaldehyde group, an ester group, an amine group, an amide group, acarbonate group, a carbamate group, a thioether group, a thioestergroup, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.

In some embodiments, R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxygroup, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; and R^(f)is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted. In some embodiments, R^(e) is H,OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substitutedor unsubstituted and R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl,any of which is substituted or unsubstituted. In some embodiments, aryl¹is 4-phenylsulfamic acid; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is heteroaryl. In some embodiments,aryl¹ is 4-phenylsulfamic acid; R^(a) is alkyl; which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is alkyl.

In some embodiments, Aryl2 is:

wherein R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a thioether group, a thioester group, athioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted, R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,alkynyl, an alkoxy group, an ether group, a carboxylic acid group, acarboxaldehyde group, an ester group, an amine group, an amide group, acarbonate group, a carbamate group, a thioether group, a thioestergroup, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted. In some embodiments, R^(e) is H, OH, F,Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I, alkyl,an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted. In some embodiments, R^(e) is H, OH, F, Cl, Br, I, alkyl,or an alkoxy group, any of which is substituted or unsubstituted; andR^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which issubstituted or unsubstituted. In some embodiments, aryl¹ is4-phenylsulfamic acid; R^(a) is alkyl, which is substituted orunsubstituted; R^(b) is arylalkyl, which is substituted orunsubstituted; R^(e) is H; and R^(f) is heteroaryl.

In some embodiments, a substituted phenyl group is:

wherein: each of R^(ph1), R^(ph2), R^(ph3), R^(ph4), and R^(ph5) isindependently H, OH, F, Cl, Br, I, CN, sulfamic acid, tosylate,mesylate, triflate, besylate, alkyl, alkenyl, alkynyl, an alkoxy group,a sulfhydryl group, a nitro group, a nitroso group, an azido group, asulfoxide group, a sulfone group, a sulfonamide group, an ether group, acarboxylic acid group, a carboxaldehyde group, an ester group, an aminegroup, an amide group, a carbonate group, a carbamate group, a thioethergroup, a thioester group, a thioacid group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Illustrative compounds include the following:

Optional Substituents for Chemical Groups.

Non-limiting examples of optional substituents include hydroxyl groups,sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups,cyano groups, azido groups, sulfoxide groups, sulfone groups,sulfonamide groups, carboxyl groups, carboxaldehyde groups, iminegroups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenylgroups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups,aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups,acyl groups, acyloxy groups, carbamate groups, amide groups, and estergroups.

Non-limiting examples of alkyl and alkylene groups include straight,branched, and cyclic alkyl and alkylene groups. An alkyl group can be,for example, a C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃,C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇,C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁,C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that is substitutedor unsubstituted.

Non-limiting examples of straight alkyl groups include methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

Branched alkyl groups include any straight alkyl group substituted withany number of alkyl groups. Non-limiting examples of branched alkylgroups include isopropyl, isobutyl, sec-butyl, and t-butyl.

Non-limiting examples of cyclic alkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctylgroups. Cyclic alkyl groups also include fused-, bridged-, andspiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclicalkyl group can be substituted with any number of straight, branched, orcyclic alkyl groups.

Non-limiting examples of alkenyl and alkenylene groups include straight,branched, and cyclic alkenyl groups. The olefin or olefins of an alkenylgroup can be, for example, E, Z, cis, trans, terminal, or exo-methylene.An alkenyl or alkenylene group can be, for example, a C₂, C₃, C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀,C₂₁, C₂₂, C₂₃, C₂₄, C₂₅, C₂₆, C₂₇, C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄,C₃₅, C₃₆, C₃₇, C₃₈, C₃₉, C₄₀, C₄₁, C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈,C₄₉, or C₅₀ group that is substituted or unsubstituted.

Non-limiting examples of alkynyl or alkynylene groups include straight,branched, and cyclic alkynyl groups. The triple bond of an alkylnyl oralkynylene group can be internal or terminal. An alkylnyl or alkynylenegroup can be, for example, a C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁,C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, C₂₀, C₂₁, C₂₂, C₂₃, C₂₄, C₂₅,C₂₆, C₂₇, C₂₈, C₂₉, C₃₀, C₃₁, C₃₂, C₃₃, C₃₄, C₃₅, C₃₆, C₃₇, C₃₈, C₃₉,C₄₀, C₄₁, C₄₂, C₄₃, C₄₄, C₄₅, C₄₆, C₄₇, C₄₈, C₄₉, or C₅₀ group that issubstituted or unsubstituted.

A halo-alkyl group can be any alkyl group substituted with any number ofhalogen atoms, for example, fluorine, chlorine, bromine, and iodineatoms. A halo-alkenyl group can be any alkenyl group substituted withany number of halogen atoms. A halo-alkynyl group can be any alkynylgroup substituted with any number of halogen atoms.

An alkoxy group can be, for example, an oxygen atom substituted with anyalkyl, alkenyl, or alkynyl group. An ether or an ether group comprisesan alkoxy group. Non-limiting examples of alkoxy groups include methoxy,ethoxy, propoxy, isopropoxy, and isobutoxy.

An aryl group can be heterocyclic or non-heterocyclic. An aryl group canbe monocyclic or polycyclic. An aryl group can be substituted with anynumber of substituents described herein, for example, hydrocarbylgroups, alkyl groups, alkoxy groups, and halogen atoms. Non-limitingexamples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl,pyridyl, imidazolyl, thiophenyl, and furyl.

An aryloxy group can be, for example, an oxygen atom substituted withany aryl group, such as phenoxy.

An aralkyl group can be, for example, any alkyl group substituted withany aryl group, such as benzyl.

An arylalkoxy group can be, for example, an oxygen atom substituted withany aralkyl group, such as benzyloxy.

A heterocycle can be any ring containing a ring atom that is not carbon,for example, N, O, S, P, Si, B, or any other heteroatom. A heterocyclecan be substituted with any number of substituents, for example, alkylgroups and halogen atoms. A heterocycle can be aromatic (heteroaryl) ornon-aromatic. Non-limiting examples of heterocycles include pyrrole,pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine,imidazole, thiophene, furan, tetrahydrofuran, pyran, andtetrahydropyran.

An acyl group can be, for example, a carbonyl group substituted withhydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl,arylalkoxy, or a heterocycle. Non-limiting examples of acyl includeacetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl,and ethoxycarbonyl.

An acyloxy group can be an oxygen atom substituted with an acyl group.An ester or an ester group comprises an acyloxy group. A non-limitingexample of an acyloxy group, or an ester group, is acetate.

A carbamate group can be an oxygen atom substituted with a carbamoylgroup, wherein the nitrogen atom of the carbamoyl group isunsubstituted, monosubstituted, or disubstituted with one or more ofhydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogenatom is disubstituted, the two substituents together with the nitrogenatom can form a heterocycle.

Pharmaceutically-Acceptable Salts.

The invention provides the use of pharmaceutically-acceptable salts ofany compound described herein. Pharmaceutically-acceptable saltsinclude, for example, acid-addition salts and base-addition salts. Theacid that is added to the compound to form an acid-addition salt can bean organic acid or an inorganic acid. A base that is added to thecompound to form a base-addition salt can be an organic base or aninorganic base. In some embodiments, a pharmaceutically-acceptable saltis a metal salt. In some embodiments, a pharmaceutically-acceptable saltis an ammonium salt.

Metal salts can arise from the addition of an inorganic base to acompound of the invention. The inorganic base consists of a metal cationpaired with a basic counterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cesium, cerium,magnesium, manganese, iron, calcium, strontium, cobalt, titanium,aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, an iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a compound of the invention. In some embodiments, the organicamine is triethyl amine, diisopropyl amine, ethanol amine, diethanolamine, triethanol amine, morpholine, N-methylmorpholine, piperidine,N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine,pyridine, pyrrazole, piprazole, imidazole, or pyrazine.

In some embodiments, an ammonium salt is a triethyl amine salt, adiisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, atriethanol amine salt, a morpholine salt, an N-methylmorpholine salt, apiperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt,a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazolesalt, a piprazole salt, an imidazole salt, or a pyrazine salt.

Acid addition salts can arise from the addition of an acid to a compoundof the invention. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In some embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucaronate salt, a saccaratesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate salt, an ethanesulfonatesalt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citratesalt, an oxalate salt, or a maleate salt.

A compound herein can be a salt of an acidic group, for example:

A compound herein can be a salt of a basic group formed from a strongacid, for example:

A compound herein can also exist in a zwitterionic form, for example:

Formulations.

A pharmaceutical composition of the disclosure can provide atherapeutically-effective amount of an activator of Tie-2.

The disclosed formulations can comprise one or morepharmaceutically-acceptable agents, which alone or in combinationsolubilize a compound herein or a pharmaceutically-acceptable saltthereof.

In some embodiments, a compound or pharmaceutically-acceptable saltthereof is present in a formulation in an amount of from about 0.1 mg/mLto about 100 mg/mL, from about 0.1 mg/mL to about 1 mg/mL, from about0.1 mg/mL to about 5 mg/mL, from about 5 mg/mL to about 10 mg/mL, fromabout 10 mg/mL to about 15 mg/mL, from about 15 mg/mL to about 20 mg/mL,from about 20 mg/mL to about 25 mg/mL, from about 25 mg/mL to about 30mg/mL, from about 30 mg/mL to about 35 mg/mL, from about 35 mg/mL toabout 40 mg/mL, from about 40 mg/mL to about 45 mg/mL,about 45 mg/mL toabout 50 mg/mL, from about 50 mg/mL to about 55 mg/mL, from about 55mg/mL to about 60 mg/mL, from about 60 mg/mL to about 65 mg/mL, fromabout 65 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 75mg/mL,about 75 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 85mg/mL, from about 85 mg/mL to about 90 mg/mL, from about 90 mg/mL toabout 95 mg/mL, or from about 95 mg/mL to about 100 mg/mL.

In some embodiments, a compound or pharmaceutically-acceptable saltthereof is present in a formulation in an amount of about 1 mg/mL, about2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL,about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11mg/mL about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20mg/mL, about 21 mg/mL about 22 mg/mL, about 23 mg/mL, about 24 mg/mL,about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29mg/mL, about 30 mg/mL, about 31 mg/mL about 32 mg/mL, about 33 mg/mL,about 34 mg/mL, about 35 mg/mL, about 36 mg/mL, about 37 mg/mL, about 38mg/mL, about 39 mg/mL, about 40 mg/mL, about 41 mg/mL about 42 mg/mL,about 43 mg/mL, about 44 mg/mL, about 45 mg/mL, about 46 mg/mL, about 47mg/mL, about 48 mg/mL, about 49 mg/mL, about 50 mg/mL, about 51 mg/mLabout 52 mg/mL, about 53 mg/mL, about 54 mg/mL, about 55 mg/mL, about 56mg/mL, about 57 mg/mL, about 58 mg/mL, about 59 mg/mL, about 60 mg/mL,about 61 mg/mL about 62 mg/mL, about 63 mg/mL, about 64 mg/mL, about 65mg/mL, about 66 mg/mL, about 67 mg/mL, about 68 mg/mL, about 69 mg/mL,about 70 mg/mL, about 71 mg/mL about 72 mg/mL, about 73 mg/mL, about 74mg/mL, about 75 mg/mL, about 76 mg/mL, about 77 mg/mL, about 78 mg/mL,about 79 mg/mL, about 80 mg/mL, about 81 mg/mL about 82 mg/mL, about 83mg/mL, about 84 mg/mL, about 85 mg/mL, about 86 mg/mL, about 87 mg/mL,about 88 mg/mL, about 89 mg/mL, about 90 mg/mL, about 91 mg/mL about 92mg/mL, about 93 mg/mL, about 94 mg/mL, about 95 mg/mL, about 96 mg/mL,about 97 mg/mL, about 98 mg/mL, about 99 mg/mL, or about 100 mg/mL.

A formulation that is disclosed herein can be made more soluble by theaddition of an additive or agent. The improvement of solubility of theformulation can increase by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 75% about 80%, about 85%,about 90%, about 95%, about 100%, about 110%, about 120%, about 130%,about 140%, about 150%, about 160%, about 170%, about 180%, about 190%,about 200%, about 225%, about 250%, about 275%, about 300%, about 325%,about 350%, about 375%, about 400%, about 450%, or about 500%.

A formulation disclosed herein can be stable for about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 4weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks,about 3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, or about one year. A formulation disclosed herein can be stable,for example, at about 0° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 60° C., about 70° C., or about 80° C.

Alcohols.

A non-limiting example of a solubilizing agent includes an organicsolvent. Non-limiting examples of organic solvents include alcohols, forexample, C₁-C₄ linear alkyl, C₃-C₄ branched alkyl, ethanol, ethyleneglycol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol,sorbitol, xylitol; substituted or unsubstituted aryl, and benzylalcohol.

Cyclodextrins.

Non-limiting examples of cyclodextrins include β-cyclodextrin, methylβ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin sodium salt, hydroxyethyl-β-cyclodextrin (HE-β-CD),heptakis (2,6-di-O-methyl)-β-cyclodextrin (DMβCD), and2-hydroxypropyl-β-cyclodextrin. A cyclodextrin can possess a largecyclic structure with a channel passing through the center of thestructure. The interior of the cyclodextrin can be hydrophobic, andinteract favorably with hydrophobic molecules. The exterior of thecyclodextrin can be highly hydrophilic owing to the several hydroxylgroups exposed to bulk solvent. Capture of a hydrophobic molecule, suchas a compound disclosed herein, in the channel of the cyclodextrin canresult in the formation of a complex stabilized by non-covalenthydrophobic interactions. The complex can be soluble in water, and carrythe captured hydrophobic molecule into the bulk solvent.

The disclosed solubilizing systems comprise2-hydroxypropyl-betα-cyclodextrin (HPβCD).2-Hydroxypropyl-β-cyclodextrin [CAS No. 128446-35-5] is commerciallyavailable as Cavitron™. 2-Hydroxypropyl-β-cyclodextrin, also describedknown as hydroxypropyl-β-cyclodextrin,2-hydroxypropyl-betα-cyclodextrin, hydroxypropyl-betα-cyclodextrin orHPβCD, can be represented by either of the following formulae:

The average molecular weight of Cavitron™, is approximately 1396 Da,wherein the average degree of substitution is from about 0.5 to about1.3 units of 2-hydroxypropyl per ring glucose unit.

In one embodiment, a formulation disclosed herein can comprise a ratioof about 20 parts of a compound herein or a pharmaceutically-acceptablesalt thereof to about 1 part solubilizing system (about 20:about 1), toabout 1 part of the compound herein or a pharmaceutically-acceptablesalt thereof to about 20 parts solubilizing system (about 1:about 20).For example, a formulation containing about 100 mg of a compound hereinor a pharmaceutically-acceptable salt thereof can contain from about 5mg to about 2000 mg of a solubilizing agent, such as a cyclodextrin. Inanother embodiment, the ratio can be based on number, or moles, orcompound compared to number, or moles, of the solubilizing system.

The following are non-limiting examples of ratios of a compound hereinand a solubilizing agent, such as a cyclodextrin. The following examplesalternatively describe the ratio of a solubilizing agent, such as acyclodextrin, and a compound herein. The ratio can be: about 20:about 1;about 19.9:about 1; about 19.8:about 1; about 19.7:about 1; about19.6:about 1; about 19.5:about 1; about 19.4:about 1; about 19.3:about1; about 19.2:about 1; about 19.1:about 1; about 19:about 1; about18.9:about 1; about 18.8:about 1; about 18.7:about 1; about 18.6:about1; about 18.5:about 1; about 18.4:about 1; about 18.3:about 1; about18.2:about 1; about 18.1:about 1; about 18:about 1; about 17.9:about 1;about 17.8:about 1; about 17.7:about 1; about 17.6:about 1; about17.5:about 1; about 17.4:about 1; about 17.3:about 1; about 17.2:about1; about 17.1:about 1; about 17:about 1; about 16.9:about 1; about16.8:about 1; about 16.7:about 1; about 16.6:about 1; about 16.5:about1; about 16.4:about 1; about 16.3:about 1; about 16.2:about 1; about16.1:about 1; about 16:about 1; about 15.9:about 1; about 15.8:about 1;about 15.7:about 1; about 15.6:about 1; about 15.5:about 1; about15.4:about 1; about 15.3:about 1; about 15.2:about 1; about 15.1:about1; about 15:about 1; about 14.9:about 1; about 14.8:about 1; about14.7:about 1; about 14.6:about 1; about 14.5:about 1; about 14.4:about1; about 14.3:about 1; about 14.2: about 1; about 14.1:about 1; about14:about 1; about 13.9:about 1; about 13.8:about 1; about 13.7:about 1;about 13.6:about 1; about 13.5:about 1; about 13.4:about 1; about13.3:about 1; about 13.2:about 1; about 13.1:about 1; about 13:about 1;about 12.9:about 1; about 12.8:about 1; about 12.7:about 1; about12.6:about 1; about 12.5:about 1; about 12.4:about 1; about 12.3:about1; about 12.2:about 1; about 12.1:about 1; about 12:about 1; about11.9:about 1; about 11.8:about 1; about 11.7:about 1; about 11.6:about1; about 11.5:about 1; about 11.4:about 1; about 11.3:about 1; about11.2:about 1; about 11.1:about 1; about 11:about 1; about 10.9:about 1;about 10.8:about 1; about 10.7:about 1; about 10.6:about 1; about10.5:about 1; about 10.4:about 1; about 10.3:about 1; about 10.2:about1; about 10.1:about 1; about 10:about 1; about 9.9:about 1; about9.8:about 1; about 9.7:about 1; about 9.6:about 1; about 9.5:about 1;about 9.4:about 1; about 9.3:about 1; about 9.2:about 1; about 9.1:about1; about 9:about 1; about 8.9:about 1; about 8.8:about 1; about8.7:about 1; about 8.6:about 1; about 8.5:about 1; about 8.4:about 1;about 8.3:about 1; about 8.2:about 1; about 8.1:about 1; about 8:about1; about 7.9:about 1; about 7.8:about 1; about 7.7:about 1; about7.6:about 1; about 7.5:about 1; about 7.4:about 1; about 7.3:about 1;about 7.2:about 1; about 7.1:about 1; about 7:about 1; about 6.9:about1; about 6.8:about 1; about 6.7:about 1; about 6.6:about 1; about6.5:about 1; about 6.4:about 1; about 6.3:about 1; about 6.2:about 1;about 6.1:about 1; about 6:about 1; about 5.9:about 1; about 5.8:about1; about 5.7:about 1; about 5.6:about 1; about 5.5:about 1; about5.4:about 1; about 5.3:about 1; about 5.2:about 1; about 5.1:about 1;about 5:about 1; about 4.9:about 1; about 4.8:about 1; about 4.7:about1; about 4.6:about 1; about 4.5:about 1; about 4.4:about 1; about4.3:about 1; about 4.2:about 1; about 4.1:about 1; about 4:about 1;about 3.9:about 1; about 3.8:about 1; about 3.7:about 1; about 3.6:about1; about 3.5:about 1; about 3.4:about 1; about 3.3:about 1; about3.2:about 1; about 3.1:about 1; about 3:about 1; about 2.9:about 1;about 2.8:about 1; about 2.7:about 1; about 2.6:about 1; about 2.5:about1; about 2.4:about 1; about 2.3:about 1; about 2.2:about 1; about2.1:about 1; about 2:about 1; about 1.9:about 1; about 1.8:about 1;about 1.7:about 1; about 1.6:about 1; about 1.5:about 1; about 1.4:about1; about 1.3:about 1; about 1.2:about 1; about 1.1:about 1; or about1:about 1.

Polyvinylpyrrolidione.

Another non-limiting example of a solubilizing agent ispolyvinylpyrrolidone (PVP), having the formula:

wherein the index n is from about 40 to about 200. PVP's can have anaverage molecular weight from about 5500 to about 28,000 g/mol. Onenon-limiting example is PVP-10, having an average molecular weight ofapproximately 10,000 g/mol.

Polyakyleneoxides and Ethers Thereof.

Another non-limiting example of solubilizing agents includespolyalkyleneoxides, and polymers of alcohols or polyols. Polymers can bemixed, or contain a single monomeric repeat subunit. For example,polyethylene glycols having an average molecular weight of from about200 to about 20,000, for example, PEG 200, PEG 400, PEG 600, PEG 1000,PEG 1450, PEG 1500, PEG 4000, PEG 4600, and PEG 8000. In a sameembodiment, a composition comprises one or more polyethylene glycolschosen from PEG 400, PEG 1000, PEG 1450, PEG 4600 and PEG 8000.

Other polyalkyleneoxides are polypropylene glycols having the formula:

HO[CH(CH₃)CH₂O]_(x)H

wherein the index x represents the average number of propyleneoxy unitsin the polymer. The index x can be represented by a whole number or afraction. For example, a polypropylene glycol having an averagemolecular weight of 8,000 g/mole (PEG 8000) can be represented by theformulae:

HO[CH(CH₃)CH₂O]₁₃₈H or HO[CH(CH₃)CH₂O]_(137.6)H

or the polypropylene glycol can be represented by the common, short handnotation: PEG 8000.

Another example of polypropylene glycols can have an average molecularweight from about 1200 g/mol to about 20,000 g/mol, i.e., apolypropylene glycol having an average molecular weight of about 8,000g/mol, for example, PEG 8000.

Another solubilizing agent is Polysorbate 80 (Tween™ 80), which is anoleate ester of sorbitol and its anhydrides copolymerized withapproximately 20 moles of ethylene oxide for each mole of sorbitol andsorbitol anhydrides. Polysorbate 80 is made up of sorbitanmono-9-octadecanoate poly(oxy-1,2-ethandiyl) derivatives.

Solubilizing agents also include poloxamers having the formula:

HO(CH₂CH₂)_(y1)(CH₂CH₂CH₂O)_(y2)(CH₂CH₂O)_(y3)OH

which are nonionic block copolymers composed of a polypropyleneoxy unitflanked by two polyethyleneoxy units. The indices y¹, y², and y³ havevalues such that the poloxamer has an average molecular weight of fromabout 1000 g/mol to about 20,000 g/mol.

Excipients.

A pharmaceutical composition of the invention can be a combination ofany pharmaceutical compounds described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, or excipients. The pharmaceuticalcomposition facilitates administration of the compound to an organism.Pharmaceutical compositions can be administered intherapeutically-effective amounts as pharmaceutical compositions byvarious forms and routes including, for example, intravenous,intravitreal, subcutaneous, intramuscular, oral, rectal, aerosol,parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal,and topical administration.

A pharmaceutical composition can be administered in a local or systemicmanner, for example, via injection of the compound directly into anorgan, optionally in a depot or sustained release formulation.Pharmaceutical compositions can be provided in the form of a rapidrelease formulation, in the form of an extended release formulation, orin the form of an intermediate release formulation. A rapid release formcan provide an immediate release. An extended release formulation canprovide a controlled release or a sustained delayed release.

For oral administration, pharmaceutical compositions can be formulatedreadily by combining the active compounds withpharmaceutically-acceptable carriers or excipients. Such carriers can beused to formulate tablets, powders, pills, dragees, capsules, liquids,gels, syrups, elixirs, slurries, suspensions and the like, for oralingestion by a subject.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Cores can be provided with suitablecoatings. For this purpose, concentrated sugar solutions can be used,which can contain an excipient such as gum 25yrazi, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or to characterize differentcombinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. In someembodiments, the capsule comprises a hard gelatin capsule comprising oneor more of pharmaceutical, bovine, and plant gelatins. A gelatin can bealkaline-processed. The push-fit capsules can contain the activeingredients in admixture with filler such as lactose, binders such asstarches, or lubricants such as talc or magnesium stearate and,stabilizers. In soft capsules, the active compounds can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. Stabilizers can be added. All formulationsfor oral administration are provided in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions can betablets, lozenges, or gels.

Parenteral injections can be formulated for bolus injection orcontinuous infusion. The pharmaceutical compositions can be in a formsuitable for parenteral injection as a sterile suspension, solution oremulsion in oily or aqueous vehicles, and can contain formulatory agentssuch as suspending, stabilizing or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. Suspensions of the activecompounds can be prepared as oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions can contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspension can also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The active compounds can be administered topically and can be formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams, and ointments. Such pharmaceutical compositions can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration of the activecompounds can employ transdermal delivery devices and transdermaldelivery patches, and can be lipophilic emulsions or buffered aqueoussolutions, dissolved or dispersed in a polymer or an adhesive. Suchpatches can be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical compounds. Transdermal delivery can beaccomplished by means of iontophoretic patches. Additionally,transdermal patches can provide controlled delivery. The rate ofabsorption can be slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically-acceptablesolvents to assist passage through the skin. For example, transdermaldevices can be in the form of a bandage comprising a backing member, areservoir containing compounds and carriers, a rate controlling barrierto deliver the compounds to the skin of the subject at a controlled andpredetermined rate over a prolonged period of time, and adhesives tosecure the device to the skin or the eye.

For administration by inhalation, the active compounds can be in a formas an aerosol, a mist, or a powder. Pharmaceutical compositions areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant,for example, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compounds and a suitablepowder base such as lactose or starch.

The compounds can also be formulated in rectal compositions such asenemas, rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, or retention enemas, containing conventional suppositorybases such as cocoa butter or other glycerides, as well as syntheticpolymers such as polyvinylpyrrolidone and PEG. In suppository forms ofthe compositions, a low-melting wax such as a mixture of fatty acidglycerides or cocoa butter can be used.

In practicing the methods of treatment or use provided herein,therapeutically-effective amounts of the compounds described herein areadministered in pharmaceutical compositions to a subject having adisease or condition to be treated. In some embodiments, the subject isa mammal such as a human. A therapeutically-effective amount can varywidely depending on the severity of the disease, the age and relativehealth of the subject, the potency of the compounds used, and otherfactors. The compounds can be used singly or in combination with one ormore therapeutic agents as components of mixtures.

Pharmaceutical compositions can be formulated using one or morephysiologically-acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations that can be used pharmaceutically. Formulation can bemodified depending upon the route of administration chosen.Pharmaceutical compositions comprising a compounds described herein canbe manufactured, for example, by mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orcompression processes.

The pharmaceutical compositions can include at least onepharmaceutically-acceptable carrier, diluent, or excipient and compoundsdescribed herein as free-base or pharmaceutically-acceptable salt form.The methods and pharmaceutical compositions described herein include theuse of crystalline forms (also known as polymorphs), and activemetabolites of these compounds having the same type of activity.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically-acceptable excipients or carriers to form asolid, semi-solid, or liquid composition. Solid compositions include,for example, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include, for example, solutionsin which a compound is dissolved, emulsions comprising a compound, or asolution containing liposomes, micelles, or nanoparticles comprising acompound as disclosed herein. Semi-solid compositions include, forexample, gels, suspensions and creams. The compositions can be in liquidsolutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionscan also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and otherpharmaceutically-acceptable additives.

Non-limiting examples of dosage forms suitable for use in the inventioninclude feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant,spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension,nanoparticle, microgel, suppository troches, aqueous or oilysuspensions, ointment, patch, lotion, dentifrice, emulsion, creams,drops, dispersible powders or granules, emulsion in hard or soft gelcapsules, syrups, phytoceuticals, nutraceuticals, and any combinationthereof.

The invention can be administered as eye drops. The average volume ofeach drop administered to a subject can be about 5 μl, about 10 μl,about 15 μl, about 20 μl, about 30 μl, about 40 μl, about 50 μl, about60 μl, about 70 μl, about 80 μl, about 90 μl, or about 100 μl. The eyedrops can contain about 0.1%, about 0.2%, about 0.3%, about 0.4%, about0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about9%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about18.5%, about 19%, about 19.5%, or about 20% of a compound of theinvention. The drops can contain about 1 mg/ml, about 5 mg/ml, about 10mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml,about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 60mg/ml, about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml,about 120 mg/ml, about 140 mg/ml, about 160 mg/ml, about 180 mg/ml, orabout 200 mg/ml of a compound of the invention. The individual doseadministered to a subject can be about 0.5 μg, about 1 μg, about 2 μg,about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg,about 9 μg, about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg,about 150 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg,about 400 μg, about 450 μg, about 500 μg, about 550 μg, about 600 μg,about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg,about 900 μg, about 950 μg, about 1 mg, about 1.1 mg, about 1.2 mg, 1.3mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8mg, about 1.9 mg, or about 2 mg of a compound of the invention. In someembodiments, more than one drop can be administered to an eye either atone time or at multiple times throughout the day.

Non-limiting examples of excipients suitable for use in eye dropsinclude cyclodextrin, α-cyclodextrin, β-cyclodextrin,2-hydroxypropyl-β-cyclodextrin (HP-β-CD), random methyl-β-cyclodextrin(RM-β-CD), sulfobutyl ether β-cyclodextrin (SBE-β-CD), γ-cyclodextrin,hydroxypropyl-γ-cyclodextrin (HP-γ-CD), hydroxyethyl-β-cyclodextrin(HE-β-CD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DMβCD), saline,sodium bisulfate, metabisulfate, ascorbic acid, acetylcysteine,benzalkonium chloride, boric acid, hyaluronic acid, hypromellose,propylene glycol, potassium sorbate, sodium chloride, sodium acetate,disodium edetate, sodium dihydrogen phosphate monohydrate, disodiumphosphate, sodium hydroxide, hydrochloric acid, glycerol, mannitol,trometamol, tyloxapol, and any combination thereof.

Non-limiting examples of pharmaceutically-acceptable excipients suitablefor use in the invention include granulating agents, binding agents,lubricating agents, disintegrating agents, sweetening agents, glidants,anti-adherents, anti-static agents, surfactants, anti-oxidants, gums,coating agents, coloring agents, flavouring agents, coating agents,plasticizers, preservatives, suspending agents, emulsifying agents,anti-microbial agents, plant cellulosic material and spheronizationagents, and any combination thereof.

A composition of the invention can be, for example, an immediate releaseform or a controlled release formulation. An immediate releaseformulation can be formulated to allow the compounds to act rapidly.Non-limiting examples of immediate release formulations include readilydissolvable formulations. A controlled release formulation can be apharmaceutical formulation that has been adapted such that drug releaserates and drug release profiles can be matched to physiological andchronotherapeutic requirements or, alternatively, has been formulated toeffect release of a drug at a programmed rate. Non-limiting examples ofcontrolled release formulations include granules, delayed releasegranules, hydrogels (e.g., of synthetic or natural origin), othergelling agents (e.g., gel-forming dietary fibers), matrix-basedformulations (e.g., formulations comprising a polymeric material havingat least one active ingredient dispersed through), granules within amatrix, polymeric mixtures, and granular masses.

The disclosed compositions can optionally comprise from about 0.001% toabout 0.005% weight by volume pharmaceutically-acceptable preservatives.One non-limiting example of a suitable preservative is benzyl alcohol.

In some, a controlled release formulation is a delayed release form. Adelayed release form can be formulated to delay a compound's action foran extended period of time. A delayed release form can be formulated todelay the release of an effective dose of one or more compounds, forexample, for about 4, about 8, about 12, about 16, or about 24 hours.

A controlled release formulation can be a sustained release form. Asustained release form can be formulated to sustain, for example, thecompound's action over an extended period of time. A sustained releaseform can be formulated to provide an effective dose of any compounddescribed herein (e.g., provide a physiologically-effective bloodprofile) over about 4, about 8, about 12, about 16 or about 24 hours.

Non-limiting examples of pharmaceutically-acceptable excipients can befound, for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa. Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), each of which is incorporated by reference in itsentirety.

The disclosed methods include administration of a Tie-2 activator, or apharmaceutically-acceptable salt thereof, in combination with apharmaceutically-acceptable carrier. The carrier can be selected tominimize any degradation of the active ingredient and to minimize anyadverse side effects in the subject.

The Tie-2 activator or a pharmaceutically-acceptable salt thereof hereincan be conveniently formulated into pharmaceutical compositions composedof one or more pharmaceutically-acceptable carriers. See e.g.,Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin MackPub. Co., Easton, Pa., which discloses typical carriers and conventionalmethods of preparing pharmaceutical compositions that can be used inconjunction with the preparation of formulations of the compounddescribed herein and which is incorporated by reference herein. Suchpharmaceuticals can be standard carriers for administration ofcompositions to humans and non-humans, including solutions such assterile water, saline, and buffered solutions at physiological pH. Othercompositions can be administered according to standard procedures. Forexample, pharmaceutical compositions can also include one or moreadditional active ingredients such as antimicrobial agents,anti-inflammatory agents, and anesthetics.

Non-limiting examples of pharmaceutically-acceptable carriers includesaline solution, Ringer's solution and dextrose solution. The pH of thesolution can be from about 5 to about 8, and can be from about 7 toabout 7.5. Further carriers include sustained release preparations suchas semipermeable matrices of solid hydrophobic polymers containing theTie-2 activator or a pharmaceutically-acceptable salt thereof, where thematrices are in the form of shaped articles, such as films, liposomes,microparticles, and microcapsules.

The disclosed methods relate to administering the Tie-2 activator or apharmaceutically-acceptable salt thereof as part of a pharmaceuticalcomposition. In various embodiments, compositions of the invention cancomprise a liquid comprising an active agent in solution, in suspension,or both. Liquid compositions can include gels. In one embodiment, theliquid composition is aqueous. Alternatively, the composition can takeform of an ointment. In another embodiment, the composition is an insitu gellable aqueous composition. In some embodiments, the compositionis an in situ gellable aqueous solution.

Pharmaceutical formulations can include additional carriers, as well asthickeners, diluents, buffers, preservatives, and surface active agentsin addition to the compounds disclosed herein. Pharmaceuticalformulations can also include one or more additional active ingredientssuch as antimicrobial agents, anti-inflammatory agents, anesthetics, andthe like.

An excipient can fill a role as simple and direct as being an inertfiller, or an excipient as used herein can be part of a pH stabilizingsystem or coating to insure delivery of the ingredients safely to thestomach.

The Tie-2 activator or a pharmaceutically-acceptable salt thereof canalso be present in liquids, emulsions, or suspensions for delivery ofactive therapeutic agents in aerosol form to cavities of the body suchas the nose, throat, or bronchial passages. The ratio of Tie-2 activatoror a pharmaceutically-acceptable salt thereof to the other compoundingagents in these preparations can vary as the dosage form requires.

Depending on the intended mode of administration, the pharmaceuticalcompositions administered as part of the disclosed methods can be in theform of solid, semi-solid or liquid dosage forms, such as, for example,tablets, suppositories, pills, capsules, powders, liquids, suspensions,lotions, creams, gels, for example, in unit dosage form suitable forsingle administration of a precise dosage. The compositions can contain,as noted above, an effective amount of the Tie-2 activator or apharmaceutically-acceptable salt thereof in combination with apharmaceutically-acceptable carrier and, in addition, can include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, diluents,etc.

For solid compositions, nontoxic solid carriers include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, and magnesiumcarbonate. In one embodiment, a composition comprising the Tie-2activator or a pharmaceutically-acceptable salt thereof in an amount ofapproximately 4 mg per 0.1 mL liquid is prepared. The liquid phasecomprises sterile water and an appropriate amount of a saccharide orpolysaccharide.

Pharmaceutical Compositions.

Pharmaceutical compositions containing the compounds described hereincan be administered for prophylactic or therapeutic treatments.Compositions can contain any number of active agents. In therapeuticapplications, the compositions can be administered to a subject alreadysuffering from a disease or condition, in an amount sufficient to cureor at least partially arrest the symptoms of the disease or condition,or to cure, heal, improve, reduce, lessen or ameliorate the disease orcondition. Compounds can also be administered to lessen or reduce alikelihood of developing, contracting, or worsening a condition. Amountseffective for this use can vary based on the severity and course of thedisease or condition, previous therapy, the subject's health status,weight, response to the drugs, and the judgment of the treatingphysician.

Multiple therapeutic agents can be administered in any order orsimultaneously. If simultaneously, the multiple therapeutic agents canbe provided in a single, unified form, or in multiple forms, forexample, as multiple separate pills or injections. The compounds can bepacked together or separately, in a single package or in a plurality ofpackages. One or all of the therapeutic agents can be given in multipledoses. If not simultaneous, the timing between the multiple doses canvary.

Compounds and compositions of the invention can be packaged as a kit. Insome embodiments, the invention provides a kit comprising a compounddisclosed herein, or a pharmaceutically-acceptable salt thereof, andwritten instructions on use of the kit in the treatment of a conditiondescribed herein. In some embodiments, the invention provides a kitcomprising a compound disclosed herein, or a pharmaceutically-acceptablesalt thereof, an antibody, and written instructions on use of the kit inthe treatment of a condition described herein.

The compounds described herein can be administered before, during, orafter the occurrence of a disease or condition, and the timing ofadministering the composition containing a compound can vary. Forexample, the compounds can be used as a prophylactic and can beadministered continuously to subjects with a propensity to conditions ordiseases in order to lessen or reduce a likelihood of the occurrence ofthe disease or condition. The compounds and compositions can beadministered to a subject during or as soon as possible after the onsetof the symptoms. The administration of the compounds can be initiatedwithin the first 48 hours of the onset of the symptoms, within the first24 hours of the onset of the symptoms, within the first 6 hours of theonset of the symptoms, or within 3 hours of the onset of the symptoms.The initial administration can be via any route practical, such as byany route described herein using any formulation described herein.

A compound can be administered as soon as is practical after the onsetof a disease or condition is detected or suspected, and for a length oftime necessary for the treatment of the disease, such as, for example,from about 1 month to about 3 months. In some embodiments, the length oftime a compound can be administered can be about 1 day, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months,about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks,about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks,about 24 weeks, about 6 months, about 7 months, about 8 months, about 9months, about 10 months, about 11 months, about 1 year, about 13 months,about 14 months, about 15 months, about 16 months, about 17 months,about 18 months, about 19 months, about 20 months, about 21 months,about 22 months about 23 months, about 2 years, about 2.5 years, about 3years, about 3.5 years, about 4 years, about 4.5 years, about 5 years,about 6 years, about 7 years, about 8 years, about 9 years, or about 10years. The length of treatment can vary for each subject.

Pharmaceutical compositions described herein can be in unit dosage formssuitable for single administration of precise dosages. In unit dosageform, the formulation is divided into unit doses containing appropriatequantities of one or more compounds. The unit dosage can be in the formof a package containing discrete quantities of the formulation.Non-limiting examples are packaged injectables, vials, or ampoules.Aqueous suspension compositions can be packaged in single-dosenon-reclosable containers. Multiple-dose reclosable containers can beused, for example, in combination with or without a preservative.Formulations for parenteral injection can be presented in unit dosageform, for example, in ampoules, or in multi-dose containers with apreservative.

A Tie-2 activator described herein can be present in a composition in arange of from about 1 mg to about 5 mg, from about 5 mg to about 10 mg,from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, fromabout 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mgto about 45 mg, from about 45 mg to about 50 mg, from about 50 mg toabout 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg,from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, fromabout 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mgto about 200 mg, from about 200 mg to about 225 mg, from about 225 mg toabout 250 mg, or from about 250 mg to about 300 mg.

A Tie-2 activator described herein can be present in a composition in anamount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about250 mg, or about 300 mg.

Treatment of Subjects with a Tie-2 Activator.

The invention discloses methods for treating a subject afflicted withelevated intraocular pressure with an activator of Tie-2. The subjectcan be a human. Treatment can include treating a human in a clinicaltrial. A treatment can comprise administering to a subject apharmaceutical composition comprising one or more of the activators ofTie-2 described throughout the disclosure. A treatment can compriseadministrating to a subject a therapy that promotes the phosphorylationof a Tie-2 molecule.

In some embodiments, the invention provides a Tie-2 activator for use intreatment of elevated intraocular pressure, ocular hypertension, orglaucoma. In some embodiments, the invention provides a Tie-2 activatorfor use in the manufacture of a medicament for the treatment of elevatedintraocular pressure, ocular hypertension, or glaucoma.

In some embodiments, the intraocular pressure or ocular hypertension iscaused by a glaucoma. In some embodiments, the glaucoma is a primaryopen angle glaucoma.

Non-limiting examples of possible subjects for administration includethe following. Subjects can be humans, non-human primates such aschimpanzees, and other apes and monkey species; farm animals such ascattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; and laboratory animals including rats, mice,and guinea pigs. A subject can be of any age. Subjects can be, forexample, elderly adults, adults, adolescents, pre-adolescents, children,toddlers, and infants.

Some conditions can lead to an increase in the levels of Ang-2, alteringthe ratio of Ang-1/Ang-2 in circulation. In some aspects, a therapy canimprove the outcome of a disease state, including increased intraocularpressure or glaucoma, by altering the ratio of Ang-1/Ang-2 incirculation. A therapy can provide an Ang-1/Ang-2 ratio or anAng-2/Ang-1 ratio of about 1:about 1, about 2:about 1, about 3:about 1,about 4:about 1, about 5:about 1, about 6:about 1, about 7:about 1,about 8:about 1, about 9:about 1, or about 10:about 1.

Pharmacodynamic and Pharmacokinetic Parameters.

Pharmacokinetic and pharmacodynamic data can be obtained by variousexperimental techniques. Appropriate pharmacokinetic and pharmacodynamicprofile components describing a particular composition can vary due tovariations in the metabolism of an activator of Tie-2 in differentsubjects. Pharmacokinetic and pharmacodynamic profiles can be based onthe determination of the mean parameters of a group of subjects. Thegroup of subjects includes any reasonable number of subjects suitablefor determining a representative mean, for example, 5 subjects, 10subjects, 15 subjects, 20 subjects, 25 subjects, 30 subjects, 35subjects, or more. The mean is determined by calculating the average ofall subject's measurements for each parameter measured.

A therapy can be used to inhibit a specific biological or biochemicalfunction at a lower dosage. A dose can be modulated to achieve a desiredpharmacokinetic or pharmacodynamics profile, such as a desired oreffective blood profile, as described herein. The half maximuminhibitory concentration (IC₅₀) is a measure of the effectiveness of asubstance in inhibiting a specific biological or biochemical function.This quantitative measure indicates how much of a particular drug orcompound is needed to inhibit a given biological process, such as theactivity of HPTPβ by half. Combination drug treatments can present lowerIC₅₀ values as compared to monotherapies.

The outcome of treating a human subject with a therapy can be measuredby calculating pharmacodynamic and pharmacokinetic parameters.Non-limiting examples of pharmacodynamic and pharmacokinetic parametersthat can be used to determine the effect of treatment of a subject witha therapy of the disclosure include: a) the amount of drug administered,which can be represented as a dose D; b) the dosing interval, which canbe represented as τ; c) the apparent volume in which a drug isdistributed, which can be represented as a volume of distribution V_(d),where V_(d)=D/C₀; d) the amount of drug in a given volume of tissue,which can be represented as concentration C₀ or C_(ss), where C₀ orC_(ss)=D/Vd; e) the half-life of a drug t_(1/2), wheret_(1/2)=ln(2)/k_(e); f) the rate at which a drug is removed from thebody k_(e), where k_(e)=ln(2)/t_(1/2)=CL/V_(d); g) the rate of infusionrequired to balance the equation K_(in), where K_(in)=C_(ss).CL; h) theintegral of the concentration-time curve after administration of asingle dose, which can be represented as AUC_(0-∞), wherein ∫₀ ^(∞) Cdt, or in steady-state, which can be represented as AUCτ_(,ss), wherein∫_(t) ^(t+π) C dt; i) the volume of tissue cleared of the drug per unittime, which can be represented as CL (clearance), whereinCL=V_(d).k_(e)=D/AUC; j) the systemically available fraction of a drug,which can be represented as f, where

$\left. {{f = \frac{{AUCpo}.{Div}}{{AUCiv}.{Dpo}}};k} \right)$

the peak tissue concentration of a drug after administration C_(max); l)the time taken by a drug to reach C_(max), t_(max); m) the lowestconcentration that a drug reaches before the next dose is administeredC_(min); and n) the peak trough fluctuation within one dosing intervalat steady state, which can be represented as % PTF=100.

${\frac{\left( {{C\; \max},{{ss} - {C\; \min}},{ss}} \right)}{{Cav},{ss}}\mspace{14mu} {where}\mspace{14mu} C_{{av},{ss}}} = {\frac{{{AUC}\; \tau},{ss}}{\tau}.}$

The pharmacokinetics parameters can be any parameters suitable fordescribing the tissue concentration profiles of a therapy of thedisclosure. For example, the pharmacokinetics profile can be obtained ata time after dosing of, for example, about zero minutes, about 1 minute,about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes,about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes,about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes,about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes,about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes,about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes,about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes,about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes,about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes,about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes,about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes,about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes,about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes,about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes,about 58 minutes, about 59 minutes, about 60 minutes, about zero hours,about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours,about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours,about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 13.5hours, about 14 hours, about 14.5 hours, about 15 hours, about 15.5hours, about 16 hours, about 16.5 hours, about 17 hours, about 17.5hours, about 18 hours, about 18.5 hours, about 19 hours, about 19.5hours, about 20 hours, about 20.5 hours, about 21 hours, about 21.5hours, about 22 hours, about 22.5 hours, about 23 hours, about 23.5hours, or about 24 hours.

The pharmacokinetic parameters can be any parameters suitable fordescribing a small molecule activator of Tie-2. The C_(max) can be, forexample, not less than about 1 ng/mL; not less than about 2 ng/mL; notless than about 3 ng/mL; not less than about 4 ng/mL; not less thanabout 5 ng/mL; not less than about 6 ng/mL; not less than about 7 ng/mL;not less than about 8 ng/mL; not less than about 9 ng/mL; not less thanabout 10 ng/mL; not less than about 15 ng/mL; not less than about 20ng/mL; not less than about 25 ng/mL; not less than about 50 ng/mL; notless than about 75 ng/mL; not less than about 100 ng/mL; not less thanabout 200 ng/mL; not less than about 300 ng/mL; not less than about 400ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; notless than about 700 ng/mL; not less than about 800 ng/mL; not less thanabout 900 ng/mL; not less than about 1000 ng/mL; not less than about1250 ng/mL; not less than about 1500 ng/mL; not less than about 1750ng/mL; not less than about 2000 ng/mL; or any other C_(max) appropriatefor describing a pharmacokinetic profile of an activator of Tie-2described herein. The C_(max) can be, for example, about 1 ng/mL toabout 5,000 ng/mL; about 1 ng/mL to about 4,500 ng/mL; about 1 ng/mL toabout 4,000 ng/mL; about 1 ng/mL to about 3,500 ng/mL; about 1 ng/mL toabout 3,000 ng/mL; about 1 ng/mL to about 2,500 ng/mL; about 1 ng/mL toabout 2,000 ng/mL; about 1 ng/mL to about 1,500 ng/mL; about 1 ng/mL toabout 1,000 ng/mL; about 1 ng/mL to about 900 ng/mL; about 1 ng/mL toabout 800 ng/mL; about 1 ng/mL to about 700 ng/mL; about 1 ng/mL toabout 600 ng/mL; about 1 ng/mL to about 500 ng/mL; about 1 ng/mL toabout 450 ng/mL; about 1 ng/mL to about 400 ng/mL; about 1 ng/mL toabout 350 ng/mL; about 1 ng/mL to about 300 ng/mL; about 1 ng/mL toabout 250 ng/mL; about 1 ng/mL to about 200 ng/mL; about 1 ng/mL toabout 150 ng/mL; about 1 ng/mL to about 125 ng/mL; about 1 ng/mL toabout 100 ng/mL; about 1 ng/mL to about 90 ng/mL; about 1 ng/mL to about80 ng/mL; about 1 ng/mL to about 70 ng/mL; about 1 ng/mL to about 60ng/mL; about 1 ng/mL to about 50 ng/mL; about 1 ng/mL to about 40 ng/mL;about 1 ng/mL to about 30 ng/mL; about 1 ng/mL to about 20 ng/mL; about1 ng/mL to about 10 ng/mL; about 1 ng/mL to about 5 ng/mL; about 10ng/mL to about 4,000 ng/mL; about 10 ng/mL to about 3,000 ng/mL; about10 ng/mL to about 2,000 ng/mL; about 10 ng/mL to about 1,500 ng/mL;about 10 ng/mL to about 1,000 ng/mL; about 10 ng/mL to about 900 ng/mL;about 10 ng/mL to about 800 ng/mL; about 10 ng/mL to about 700 ng/mL;about 10 ng/mL to about 600 ng/mL; about 10 ng/mL to about 500 ng/mL;about 10 ng/mL to about 400 ng/mL; about 10 ng/mL to about 300 ng/mL;about 10 ng/mL to about 200 ng/mL; about 10 ng/mL to about 100 ng/mL;about 10 ng/mL to about 50 ng/mL; about 25 ng/mL to about 500 ng/mL;about 25 ng/mL to about 100 ng/mL; about 50 ng/mL to about 500 ng/mL;about 50 ng/mL to about 100 ng/mL; about 100 ng/mL to about 500 ng/mL;about 100 ng/mL to about 400 ng/mL; about 100 ng/mL to about 300 ng/mL;or about 100 ng/mL to about 200 ng/mL.

The T_(max) of an activator of Tie-2 described herein can be, forexample, not greater than about 0.5 hours, not greater than about 1hours, not greater than about 1.5 hours, not greater than about 2 hours,not greater than about 2.5 hours, not greater than about 3 hours, notgreater than about 3.5 hours, not greater than about 4 hours, notgreater than about 4.5 hours, not greater than about 5 hours, or anyother T_(max) appropriate for describing a pharmacokinetic profile of anactivator of Tie-2 described herein. The T_(max) can be, for example,about 0.1 hours to about 24 hours; about 0.1 hours to about 0.5 hours;about 0.5 hours to about 1 hour; about 1 hour to about 1.5 hours; about1.5 hours to about 2 hour; about 2 hours to about 2.5 hours; about 2.5hours to about 3 hours; about 3 hours to about 3.5 hours; about 3.5hours to about 4 hours; about 4 hours to about 4.5 hours; about 4.5hours to about 5 hours; about 5 hours to about 5.5 hours; about 5.5hours to about 6 hours; about 6 hours to about 6.5 hours; about 6.5hours to about 7 hours; about 7 hours to about 7.5 hours; about 7.5hours to about 8 hours; about 8 hours to about 8.5 hours; about 8.5hours to about 9 hours; about 9 hours to about 9.5 hours; about 9.5hours to about 10 hours; about 10 hours to about 10.5 hours; about 10.5hours to about 11 hours; about 11 hours to about 11.5 hours; about 11.5hours to about 12 hours; about 12 hours to about 12.5 hours; about 12.5hours to about 13 hours; about 13 hours to about 13.5 hours; about 13.5hours to about 14 hours; about 14 hours to about 14.5 hours; about 14.5hours to about 15 hours; about 15 hours to about 15.5 hours; about 15.5hours to about 16 hours; about 16 hours to about 16.5 hours; about 16.5hours to about 17 hours; about 17 hours to about 17.5 hours; about 17.5hours to about 18 hours; about 18 hours to about 18.5 hours; about 18.5hours to about 19 hours; about 19 hours to about 19.5 hours; about 19.5hours to about 20 hours; about 20 hours to about 20.5 hours; about 20.5hours to about 21 hours; about 21 hours to about 21.5 hours; about 21.5hours to about 22 hours; about 22 hours to about 22.5 hours; about 22.5hours to about 23 hours; about 23 hours to about 23.5 hours; or about23.5 hours to about 24 hours.

The AUC_((0-inf)) or AUC_((last)) of an activator of Tie-2 describedherein can be, for example, not less than about 1 ng·hr/mL, not lessthan about 5 ng·hr/mL, not less than about 10 ng·hr/mL, not less thanabout 20 ng·hr/mL, not less than about 30 ng·hr/mL, not less than about40 ng·hr/mL, not less than about 50 ng·hr/mL, not less than about 100ng·hr/mL, not less than about 150 ng·hr/mL, not less than about 200ng·hr/mL, not less than about 250 ng·hr/mL, not less than about 300ng·hr/mL, not less than about 350 ng·hr/mL, not less than about 400ng·hr/mL, not less than about 450 ng·hr/mL, not less than about 500ng·hr/mL, not less than about 600 ng·hr/mL, not less than about 700ng·hr/mL, not less than about 800 ng·hr/mL, not less than about 900ng·hr/mL, not less than about 1000 ng·hr/mL, not less than about 1250ng·hr/mL, not less than about 1500 ng·hr/mL, not less than about 1750ng·hr/mL, not less than about 2000 ng·hr/mL, not less than about 2500ng·hr/mL, not less than about 3000 ng·hr/mL, not less than about 3500ng·hr/mL, not less than about 4000 ng·hr/mL, not less than about 5000ng·hr/mL, not less than about 6000 ng·hr/mL, not less than about 7000ng·hr/mL, not less than about 8000 ng·hr/mL, not less than about 9000ng·hr/mL, not less than about 10,000 ng·hr/mL, or any otherAUC_((0-inf)) appropriate for describing a pharmacokinetic profile of acompound described herein. The AUC_((0-inf)) of an activator of Tie-2can be, for example, about 1 ng·hr/mL to about 10,000 ng·hr/mL; about 1ng·hr/mL to about 10 ng·hr/mL; about 10 ng·hr/mL to about 25 ng·hr/mL;about 25 ng·hr/mL to about 50 ng·hr/mL; about 50 ng·hr/mL to about 100ng·hr/mL; about 100 ng·hr/mL to about 200 ng·hr/mL; about 200 ng·hr/mLto about 300 ng·hr/mL; about 300 ng·hr/mL to about 400 ng·hr/mL; about400 ng·hr/mL to about 500 ng·hr/mL; about 500 ng·hr/mL to about 600ng·hr/mL; about 600 ng·hr/mL to about 700 ng·hr/mL; about 700 ng·hr/mLto about 800 ng·hr/mL; about 800 ng·hr/mL to about 900 ng·hr/mL; about900 ng·hr/mL to about 1,000 ng·hr/mL; about 1,000 ng·hr/mL to about1,250 ng·hr/mL; about 1,250 ng·hr/mL to about 1,500 ng·hr/mL; about1,500 ng·hr/mL to about 1,750 ng·hr/mL; about 1,750 ng·hr/mL to about2,000 ng·hr/mL; about 2,000 ng·hr/mL to about 2,500 ng·hr/mL; about2,500 ng·hr/mL to about 3,000 ng·hr/mL; about 3,000 ng·hr/mL to about3,500 ng·hr/mL; about 3,500 ng·hr/mL to about 4,000 ng·hr/mL; about4,000 ng·hr/mL to about 4,500 ng·hr/mL; about 4,500 ng·hr/mL to about5,000 ng·hr/mL; about 5,000 ng·hr/mL to about 5,500 ng·hr/mL; about5,500 ng·hr/mL to about 6,000 ng·hr/mL; about 6,000 ng·hr/mL to about6,500 ng·hr/mL; about 6,500 ng·hr/mL to about 7,000 ng·hr/mL; about7,000 ng·hr/mL to about 7,500 ng·hr/mL; about 7,500 ng·hr/mL to about8,000 ng·hr/mL; about 8,000 ng·hr/mL to about 8,500 ng·hr/mL; about8,500 ng·hr/mL to about 9,000 ng·hr/mL; about 9,000 ng·hr/mL to about9,500 ng·hr/mL; or about 9,500 ng·hr/mL to about 10,000 ng·hr/mL.

The concentration in a tissue or fluid of an eye of an activator ofTie-2 described herein can be determined, for example, the intraocularconcentration or amount. Non-limiting examples of tissues of the eyeinclude cornea, iris, zonule fibers, sclera, lens, vitreous humor,fovea, choroid, ciliary muscle, aqueous humor, retina, and optic nerve.The concentration in the tissue of the eye of an activator of Tie-2described herein can be, for example, about 0.1 nanograms per gram(ng/g), about 0.2 ng/g, about 0.3 ng/g, about 0.4 ng/g, about 0.5 ng/g,about 0.6 ng/g, about 0.7 ng/g, about 0.9 ng/g, about 1 ng/g, about 2ng/g, about 3 ng/g, about 4 ng/g, about 5 ng/g, about 6 ng/g, about 7ng/g, about 9 ng/g, about 10 ng/g, about 20 ng/g, about 30 ng/g, about40 ng/g, about 50 ng/g, about 60 ng/g, about 70 ng/g, about 90 ng/g,about 0.1 micrograms per gram (μg/g), about 0.2 μg/g, about 0.3 μg/g,about 0.4 μg/g, about 0.5 μg/g, about 0.6 μg/g, about 0.7 μg/g, about0.9 μg/g, about 1 μg/g, about 2 μg/g, about 3 μg/g, about 4 μg/g, about5 μg/g, about 6 μg/g, about 7 μg/g, about 9 μg/g, about 10 μg/g, about20 μg/g, about 30 μg/g, about 40 μg/g, about 50 μg/g, about 60 μg/g,about 70 μg/g, about 90 μg/g, about 0.1 milligrams per gram (mg/g),about 0.2 mg/g, about 0.3 mg/g, about 0.4 mg/g, about 0.5 mg/g, about0.6 mg/g, about 0.7 mg/g, about 0.9 mg/g, or about 1 mg/g tissue weight.

The concentration in the tissue of the eye of an activator of Tie-2described herein can be, for example, from about 0.1 ng/g to about 0.2ng/g, from about 0.2 ng/g to about 0.3 ng/g, from about 0.3 ng/g toabout 0.4 ng/g, from about 0.4 ng/g to about 0.5 ng/g, from about 0.5ng/g to about 0.6 ng/g, from about 0.6 ng/g to about 0.7 ng/g, fromabout 0.7 ng/g to about 0.8 ng/g, from about 0.8 ng/g to about 0.9 ng/g,from about 0.9 ng/g to about 1 ng/g, from about 1 ng/g to about 2 ng/g,from about 2 ng/g to about 3 ng/g, from about 3 ng/g to about 4 ng/g,from about 4 ng/g to about 5 ng/g, from about 5 ng/g to about 6 ng/g,from about 6 ng/g to about 7 ng/g, from about 7 ng/g to about 8 ng/g,from about 8 ng/g to about 9 ng/g, from about 9 ng/g to about 10 ng/g,from about 10 ng/g to about 20 ng/g, from about 20 ng/g to about 30ng/g, from about 30 ng/g to about 40 ng/g, from about 40 ng/g to about50 ng/g, from about 50 ng/g to about 60 ng/g, from about 60 ng/g toabout 70 ng/g, from about 70 ng/g to about 80 ng/g, from about 80 ng/gto about 90 ng/g, from about 90 ng/g to about 0.1 μg/g, from about 0.1μg/g to about 0.2 μg/g, from about 0.2 μg/g to about 0.3 μg/g, fromabout 0.3 μg/g to about 0.4 μg/g, from about 0.4 μg/g to about 0.5 μg/g,from about 0.5 μg/g to about 0.6 μg/g, from about 0.6 μg/g to about 0.7μg/g, from about 0.7 μg/g to about 0.8 μg/g, from about 0.8 μg/g toabout 0.9 μg/g, from about 0.9 μg/g to about 1 μg/g, from about 1 μg/gto about 2 μg/g, from about 2 μg/g to about 3 μg/g, from about 3 μg/g toabout 4 μg/g, from about 4 μg/g to about 5 μg/g, from about 5 μg/g toabout 6 μg/g, from about 6 μg/g to about 7 μg/g, from about 7 μg/g toabout 8 μg/g, from about 8 μg/g to about 9 μg/g, from about 9 μg/g toabout 10 μg/g, from about 10 μg/g to about 20 μg/g, from about 20 μg/gto about 30 μg/g, from about 30 μg/g to about 40 μg/g, from about 40μg/g to about 50 μg/g, from about 50 μg/g to about 60 μg/g, from about60 μg/g to about 70 μg/g, from about 70 μg/g to about 80 μg/g, fromabout 80 μg/g to about 90 μg/g, from about 90 μg/g to about 0.1 mg/g,from about 0.1 mg/g to about 0.2 mg/g, from about 0.2 mg/g to about 0.3mg/g, from about 0.3 mg/g to about 0.4 mg/g, from about 0.4 mg/g toabout 0.5 mg/g, from about 0.5 mg/g to about 0.6 mg/g, from about 0.6mg/g to about 0.7 mg/g, from about 0.7 mg/g to about 0.8 mg/g, fromabout 0.8 mg/g to about 0.9 mg/g, or from about 0.9 mg/g to about 1 mg/gtissue weight.

Administration of a Tie-2 activator to the eye can reduce theintraocular pressure, for example, by about 0.1 mmHg, about 0.2 mmHg,about 0.3 mmHg, about 0.4 mmHg, about 0.5 mmHg, about 0.6 mmHg, about0.7 mmHg, about 0.8 mmHg, about 0.9 mmHg, about 1 mmHg, about 1.1 mmHg,about 1.2 mmHg, about 1.3 mmHg, about 1.4 mmHg, about 1.5 mmHg, about1.6 mmHg, about 1.7 mmHg, about 1.8 mmHg, about 1.9 mmHg, about 2 mmHg,about 2.1 mmHg, about 2.2 mmHg, about 2.3 mmHg, about 2.4 mmHg, about2.5 mmHg, about 2.6 mmHg, about 2.7 mmHg, about 2.8 mmHg, about 2.9mmHg, about 3 mmHg, about 3.1 mmHg, about 3.2 mmHg, about 3.3 mmHg,about 3.4 mmHg, about 3.5 mmHg, about 3.6 mmHg, about 3.7 mmHg, about3.8 mmHg, about 3.9 mmHg, about 4 mmHg, about 4.1 mmHg, about 4.2 mmHg,about 4.3 mmHg, about 4.4 mmHg, about 4.5 mmHg, about 4.6 mmHg, about4.7 mmHg, about 4.8 mmHg, about 4.9 mmHg, about 5 mmHg, about 5.1 mmHg,about 5.2 mmHg, about 5.3 mmHg, about 5.4 mmHg, about 5.5 mmHg, about5.6 mmHg, about 5.7 mmHg, about 5.8 mmHg, about 5.9 mmHg, about 6 mmHg,about 6.1 mmHg, about 6.2 mmHg, about 6.3 mmHg, about 6.4 mmHg, about6.5 mmHg, about 6.6 mmHg, about 6.7 mmHg, about 6.8 mmHg, about 6.9mmHg, about 7 mmHg, about 7.1 mmHg, about 7.2 mmHg, about 7.3 mmHg,about 7.4 mmHg, about 7.5 mmHg, about 7.6 mmHg, about 7.7 mmHg, about7.8 mmHg, about 7.9 mmHg, about 8 mmHg, about 8.1 mmHg, about 8.2 mmHg,about 8.3 mmHg, about 8.4 mmHg, about 8.5 mmHg, about 8.6 mmHg, about8.7 mmHg, about 8.8 mmHg, about 8.9 mmHg, about 9 mmHg, about 9.1 mmHg,about 9.2 mmHg, about 9.3 mmHg, about 9.4 mmHg, about 9.5 mmHg, about9.6 mmHg, about 9.7 mmHg, about 9.8 mmHg, about 9.9 mmHg, about 10 mmHg,about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, orabout 20 mmHg

Administration of a Tie-2 activator to the eye can reduce theintraocular pressure, for example, by at least 20 mmHg, by about 0.1mmHg to about 20 mmHg, by about 0.1 mmHg to about 15 mmHg, by about 0.1mmHg to about 10 mmHg, by about 0.1 mmHg to about 9 mmHg, by about 0.1mmHg to about 8 mmHg, by about 0.1 mmHg to about 7 mmHg, by about 0.1mmHg to about 6 mmHg, by about 0.1 mmHg to about 5 mmHg, by about 0.1mmHg to about 4 mmHg, by about 0.1 mmHg to about 3 mmHg, by about 0.1mmHg to about 2 mmHg, by about 0.1 mmHg to about 1 mmHg, by about 0.5mmHg to about 20 mmHg, by about 0.5 mmHg to about 15 mmHg, by about 0.5mmHg to about 10 mmHg, by about 0.5 mmHg to about 9 mmHg, by about 0.5mmHg to about 8 mmHg, by about 0.5 mmHg to about 7 mmHg, by about 0.5mmHg to about 6 mmHg, by about 0.5 mmHg to about 5 mmHg, by about 0.5mmHg to about 4 mmHg, by about 0.5 mmHg to about 3 mmHg, by about 0.5mmHg to about 2 mmHg, by about 0.5 mmHg to about 1 mmHg, by about 1 mmHgto about 20 mmHg, by about 1 mmHg to about 15 mmHg, by about 1 mmHg toabout 10 mmHg, by about 1 mmHg to about 9 mmHg, by about 1 mmHg to about8 mmHg, by about 1 mmHg to about 7 mmHg, by about 1 mmHg to about 6mmHg, by about 1 mmHg to about 5 mmHg, by about 1 mmHg to about 4 mmHg,by about 1 mmHg to about 3 mmHg, or by about 1 mmHg to about 2 mmHg.

Administration of a Tie-2 activator can be topical, such as in an eyedrop unit dosage form, based on several findings. In an in vitro study,a formulation of a Tie-2 activator Compound 1 (1.5% of the sodium saltwith 5% HPβCD in 50:50 D5W:sterile water) demonstrated substantialdiffusion across a rabbit cornea and sclera in Franz cell. In an in vivostudy in mice, three topical doses of a Tie-2 activator (Compound 1 at40 mg/mL in 10% HPβCD) led to accumulation of about 20 micrograms pergram (μg/g) tissue to 30 μg/g tissue in the choroid and retina. In an invivo study in rabbits, after three topical doses of a Tie-2 activator(Compound 1 at 40 mg/mL in 10% HPβCD) retinal and choroid levels of theTie-2 activator were about 341 nanograms per gram (ng/g) and 76 ng/g,respectively. In another in vivo study in rabbits, after three topicaldoses of the Tie-2 activator Compound 1 at 40 mg/mL in 10% HPβCD or 20mg/mL in 5% dextrose, choroid levels were 8.87 ng/g and 4.31 ng/g,respectively, for the 40 mg/mL and 20 mg/mL formulations at one hourafter the last dose. Retina levels were 4.45 ng/g and a.37 ng/g,respectively, for the 40 mg/mL and 20 mg/mL formulations at one hourafter the last dose.

Treatment of Intraocular Pressure with a Tie-2 Activator

FIG. 1 shows the effect of administration of a Tie-2 activator(Compound 1) delivered twice daily (BID) at varying doses on intraocularpressure (IOP) relative to a pre-treatment baseline. The difference inIOP was determined at the end of the trial, which was 28 days aftertreatment began (28 Day EOT). Changes in IOP were determined both in thestudy eye and the fellow eye. Doses greater than 15 mg BID of Compound 1resulted in decreased IOP in patients with diabetic macular edema.

FIG. 2 shows the effect on intraocular pressure of administration of aTie-2 activator (Compound 1) combined with a sham treatment; Compound 1combined with ranibizumab (RBZ); a placebo combined with RBZ; or thecombined results of both Compound 1 treatment groups. The difference inIOP was determined relative to a pre-treatment baseline (Base) at months1, 2, and 3 (M1-M3). Intraocular pressure was determined in the studyeye in millimeters of mercury (mmHg).

TABLE 1 shows the effect of shows the effect on intraocular pressure ofadministration of: 1) Compound 1 combined with a sham treatment(Compound 1+ sham); 2) Compound 1 combined with ranibizumab (Compound 1+RBZ); or 3) a placebo combined with RBZ (placebo+RBZ). The difference inIOP was determined relative to a pre-treatment Baseline at Months 1, 2,and 3. Intraocular pressure was determined in the study eye/fellow eyein mmHg.

TABLE 1 Compound Compound IOP/Treatment arm 1 + sham 1 + RBZ placebo +RBZ Baseline 15.8/15.4 15.9/16.1 15.2/15.8 Month 1 14.8/14.5 14.7/14.415.0/15.5 Month 2 14.4/14.3 14.6/14.7 15.0/15.5 Month 3 14.3/14.015.1/14.7 15.3/15.7

EXAMPLES Example 1 Compounds with Inhibitory Activity to HPTP-β

Non-limiting examples of the HPTP-β IC₅₀ (μM) activity for illustrativecompounds are listed in TABLE 2.

TABLE 2 HPTP-β No. Compound IC₅₀ μM AA1

0.000157 (S)-{4-[2-(4-Ethylthiazol-2-yl)-2-(phenylacetylamino)ethyl]-phenyl}sulfamic acid AA2

0.004 4-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acid AA3

0.031 {1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoyl]-(S)-2- phenylethyl}methyl carbamicacid tert-butyl ester AA4

<5 × 10⁻⁸ {1-[1-(5-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2- phenylethyl}methyl carbamic acidtert-butyl ester AA5

<5 × 10⁻⁸ 4-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido-2-(2-phenylthiazol-4- yl)}phenylsulfamic acid AA6

0.000162 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA7

0.006 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(thiazol-2- yl)ethyl}phenylsulfamic acid AA8

0.001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-methylthiazol-2- yl)ethyl}phenylsulfamic acidAA9

0.0001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-propylthiazol-2- yl)ethyl}phenylsulfamic acidAA10

0.0002 4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA11

0.00001 4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acid AA12

<5 × 10⁻⁸ 4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA13

0.001 4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA14

0.0001 4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA15

0.0003 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid AA16

0.00008 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanam]do)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]et]yl}phenylsulfamic acid AA17

0.001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(methoxymethyl)thiazol-2-yl]ethyl}phenylsulfamic acid AA18

0.0002 4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA19

0.0003 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(5-phenylthiazol-2- yl)ethyl}phenylsulfamic acidAA20

<5 × 10⁻⁸ 4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonylamino)-3-phenyl- propanamido]ethyl}phenylsulfamic acidAA21

<2 × 10⁻⁶ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-phenylthiazol-2- yl)ethyl}phenylsulfamic acidAA22

<5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamic acid AA23

0.00009 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid AA24

0.001 4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamicacid AA25

0.0004 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic acid AA26

<5 × 10⁻⁸ 4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenyl-sulfamic acidAA27

0.00014 4-{(S)-2-[(S)-2-(Ethoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acidAA28

0.0001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl) ethyl}phenylsulfamic acidAA29

0.001 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylthiazol-4- yl)ethyl}phenylsulfamic acidAA30

0.0002 4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acid AA31

0.00008 4-{(S)-2-{2[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid AA32

0.002 4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamicacid AA33

  7 × 10⁻⁷ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido}-2-(2-phenylthiazole-4- yl)ethyl}phenylsulfamic acidAA34

  5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid AA35

<5 × 10⁻⁸ 4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acidAA36

<5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid AA37

0.0004 4-{[(S)-2-(2-(Furan-2-yl)thiazol-4)yl]-2-[(S)-2-(methoxy-carbonylamino)-3- phenylpropanamido]ethyl}phenylsulfamic acid AA38

0.003 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(pyrazin-2-yl)thiazol-4- yl]ethyl}phenylsulfamicacid AA39

0.001 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid AA40

0.0003 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamic acid AA41

0.00024 4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid AA42

0.006 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acid AA43

0.028 (S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid AA44

0.020 (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonylamino)acetamido]ethyl}phenylsulfamic acid AA45

0.003 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-methylbutanamido]- ethyl}phenylsulfamic acidAA46

0.001 4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethylthiazol-2- yl)ethyl}phenylsulfamic acidAA47

0.0003 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-4- methylpentanamido]ethyl}phenylsulfamic acidAA48

0.0003 4-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-{2-(methoxycarbonylamino)-acetamido]-3-phenylpropanamido}ethyl)phenylsulfamic acid AA49

<5 × 10⁻⁸ 4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid AA50

0.028 (S)-4-{2-[2-(tert-Butoxycarbonylamino)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamic acid AA51

0.049 [1-(S)-(Phenylthiazol-2-yl)-2-(4- sulfoaminophenyl)ethyl]-carbamic acid tert-butyl ester AA52

0.112 (S)-4-(2-(4-Methylthiazol-2-yl)-2- pivalamidoethyl)phenyl-sulfamicacid AA53

0.085 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamidoethyl)phenyl- sulfamicacid AA54

0.266 (S)-4-{2-[4-(hydroxymethyl)thiazol-2-yl]-2-pivalamidoethyl}phenyl-sulfamic acid AA55

0.584 (S)-4-{[2-(4-Ethoxycarbonyl)thiazol-2-yl]-2-pivalamidoethyl}phenylsulfamic acid AA56

0.042 (S)-4-(2-(4-Phenylthiazol-2-yl)-2- pivalamidoethyl)phenylsulfamicacid AA57

0.110 4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA58

0.086 4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamic acid AA59

0.113 (S)-4-(2-(4-Benzylthiazol-2-yl)-2- pivalamidoethyl)phenylsulfamicacid AA60

0.132 (S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA61

0.138 4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA62

0.098 (S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA63

0.381 (S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid AA64

0.033 (S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamic acid AA65

0.04 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-propylthiazol-2-yl)ethyl)phenyl sulfamic acid AA66

0.027 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-tert-butylthiazol-2-yl)ethyl)phenyl sulfamic acid AA67

0.18 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid AA68

0.644 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(hydroxymethyl)thiazol-2-yl)ethyl)phenylsulfamic acid AA69

0.167 (S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylsulfamic acid AA70

0.132 (S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(2-(2-methoxy-2- oxoyethylamino)-2-oxoethyl)thiazole-2- yl)ethyl)phenylsulfamic acid AA71

0.555 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-pivalamidothiazol-4-yl)ethyl)phenylsulfamic acid AA72

0.308 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenyl sulfamic acid AA73

0.253 4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid AA74

0.045 4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenyl sulfamic acid AA75

0.05 (S)-{4-[2-(4-Ethylthiazol-2-yl)-2-(phenylacetylamido)ethyl]-phenyl}sulfamic acid AA76

0.012 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid AA77

0.0003 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)phenyl-sulfamic acid AA78

0.028 (S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA79

0.075 (S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA80

0.056 (S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA81

0.033 (S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA82

0.04 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phenyl-sulfamic acid AA83

0.014 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid AA84

0.008 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phenyl-sulfamic acid AA85

0.002 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfamic acid AA86

0.028 (S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid AA87

0.037 (S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsulfamic acid AA88

0.0002 (S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenyl-sulfamic acid AA89

0.003 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid AA90

0.01 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid AA91

0.006 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)phenyl-sulfamic acid AA92

0.002 (S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid AA93

0.002 (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)acetamide]ethyl}phenylsulfamic acid AA94

0.042 (S)-4-[2-(Benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid AA95

0.003 (S)-4-(2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)phenylsulfamic acid AA96

0.046 (S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl)-phenylsulfamic acid AA97

0.0002 4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid AA98

0.0006 4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid AA99

0.002 4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4- yl)ethyl)phenylsulfamic acidAA100

  9 × 10⁻⁶ 4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid

Example 2 Ocular Pharmacokinetics After Administration of Compound 1

To measure the concentration of Compound 1 in plasma and ocular tissuesfollowing topical ocular, subcutaneous, and intravitreal administration,New Zealand White rabbits were administered Compound 1, and plasma andocular samples were collected at pre-determined time points. Compound 1formulations were prepared fresh on each day of dosing.

Ocular tissue samples from both eyes of each animal were collected andweights were recorded. Plasma and ocular tissue sample concentrations ofCompound 1 were determined by LC-MS/MS.

New Zealand White rabbits weighing 2.5 to 3.5 kg were used on thisstudy. Rabbits were housed one per cage. Animals were not fasted andonly healthy animals with no ocular illness were used. Two rabbits pergroup were sacrificed at each of four ocular tissue sampling time pointsfor a total of eight rabbits per group. The study design is presented inTABLE 3 and TABLE 4.

Animals were anesthetized for ocular (topical) and intravitreal dosingfollowing the 12IA7 IACUC protocol. Each rabbit received a bolus dose oftest formulation either via topical ocular administration 3 times dailyon Days 1 and 2 (at 0, 6, and 12 hours), and once on Day 3 (at 0 hours)into both eyes; via intravitreal administration into both eyes once onDay 1 (at 0 hours); or via subcutaneous administration 2 times daily onDays 1 and 2 (at 0 and 8 hours) and once daily on Day 3 (at 0 hours).Doses were given within an approximately 1 hour window each day whereapplicable.

Pre-screening clinical ophthalmic exams were done prior to study(includes slit-lamp biomicroscopy and indirect ophthalmoscopy). Ocularfindings were scored using the McDonald-Shadduck Score System, and onlyanimals that scored zero in all categories were used in the study.

On Day 1, for intravitreal administration, or on Day 3, for topicalocular and subcutaneous administration, at the appropriate ocular tissuecollection time points, animals were euthanized and both eyes wereenucleated immediately. Following enucleation, each eye was rinsed withphosphate-buffered saline. Ocular tissue samples from both eyes of eachanimal were collected at predetermined time points and weights wererecorded. All the samples were frozen immediately on dry ice, and storedat −60° C. to −80° C. pending bioanalysis.

Each blood sample was collected on Day 3 post dose at pre-determinedtime points from the rabbits via an ear vessel and placed into chilledpolypropylene tubes containing sodium heparin as an anticoagulant.Samples were spun by centrifuge at 4° C. and 3,000× g for 5 minutes.Samples were maintained chilled throughout processing. Each plasmasample was placed on dry ice and stored in a freezer at −60° C. to −80°C. pending bioanalysis.

TABLE 3 and TABLE 4 show a summary of the study design.

TABLE 3 Animals Dose Test Dosing per time Total Dosing group compoundroute point N= animals regimen Dose 1 Compound 1 Topical 2 8 Day 1: 0,6, 1.2 mg sodium salt ocular and 12 hr; per eye (OU) Day 2: 0, 6, and 12hr; Day 3: 0 hr 2 Compound 1 Subcutaneous 2 8 Day 1: 0 and 5 mg/kgsodium salt 8 hr; Day 2: 0 and 8 hr; Day 3: 0 hr 3 Compound 1Subcutaneous 2 8 Day 1: 0 hr; 5 mg/kg free acid Day 2: 0 hr; Day 3: 0 hr4 Compound 1 Intravitreal 2 8 Day 1: 0 hr 2.5 mg sodium salt (OU) pereye 5 Compound 1 Intravitreal 2 8 Day 1: 0 hr 2.5 mg free acid (OU) pereye OU: both eyes

TABLE 4 Plasma Ocular tissue Dose Dosing formulation Dosing samplingtime sampling time group conc. volume Vehicle points (Day 3) points (Day3) 1 40 mg/mL (solution) 30 μL per eye 15% HPβCD + 1% 30 min; 1, 2, and30 min, 1, 2, and dextrose in water 4 hr 4 hr 2 40 mg/mL (solution)0.125 mL/kg 15% HPβCD + 1% 15* and 30 min; 30 min, 1, 2, and dextrose inwater 1, 2, and 4 hr 4 hr 3 25 mg/mL (solution) 0.2 mL/kg 40 mMphosphate 15* and 30 min; 30 min, 1, 2, and buffer pH 4.0 + 1, 2, and 4hr 4 hr 2.5% dextrose in water 4 25 mg/mL (solution) 100 μL per eye 10%HPβCD + 2% 1**, 3**, 6, and 6, 24, 48, and 72 dextrose in water 24 hrhours 5 25 mg/mL (solution) 100 μL per eye 40 mM phosphate 1**, 3**, 6,and 6, 24, 48, and 72 buffer pH 4.0 + 24 hr hours 2.5% dextrose in water*Rabbits from the 30 minute ocular tissue sampling time point were bledat 15 minutes post dose. **Rabbits from the 48 hour ocular tissuesampling time point were bled for the 1 hour plasma sampling. Rabbitsfrom the 72 hour ocular tissue sampling time point were bled for the 3hour plasma sampling. HPβCD: hydroxypropyl-beta-cyclodextrin

An LC-MS/MS method was developed for the determination of Compound 1 inrabbit aqueous tissues (plasma, aqueous and vitreous humor) and solidocular tissue samples. A pre-study standard curve was analyzed todetermine the specificity, range, and lower limit of quantitation of themethod. Plasma and tissue homogenate study samples were extracted andanalyzed. All the samples were treated identically to the standards.

One eight-point standard curve was used in each analytical batch. To beaccepted, each batch must have had at least five of eight standards withaccuracy within ±20% of nominal, except at the lower limit ofquantification (LLOQ), where ±25% was acceptable.

Pharmacokinetic parameters were calculated from the time course of theplasma concentration. The maximum plasma concentration (C_(max)) andtime to the maximum plasma drug concentration (T_(max)) were theobserved values for each concentration-time profiles. The area under theplasma drug concentration-time curve (AUC_(last), with last being fromtime 0 to the last quantifiable point) was calculated using thetrapezoidal formula. The mean residence time MRT_(last) was calculatedas a ratio of AUMC_(last) (area under the first movement curve) toAUC_(last).

No ocular abnormalities were noted in any animals in any of the dosegroups.

Individual and average concentrations for Compound 1 are shown in TABLES5-18. Concentration versus time data is plotted in FIGS. 3-16. All dataare expressed as ng/g of the free drug. Samples that were below thelimit of quantitation (0.2 ng/mL) were not used in the calculation ofaverages.

As seen in FIG. 3, topical ocular administration of the sodium salt ofCompound 1 resulted in an increase in Compound 1 plasma concentration asmeasured at the 4 hour mark. As seen in FIG. 4, subcutaneousadministration of the sodium salt of Compound 1 resulted in generallyincreased plasma concentrations as compared to the free acid up to onehour post-administration. As seen in FIG. 5, intravitreal administrationof the sodium salt of Compound 1 resulted in slightly higher plasmaconcentrations as compared to the free acid up to twenty-four hourspost-administration. As seen in FIG. 6, topical ocular administration ofCompound 1 (sodium salt) resulted in aqueous humor concentrations ofbelow 50 ng/g of Compound 1 over four hours. As seen in FIG. 7,subcutaneous administration of the sodium salt of Compound 1 resulted inincreased aqueous humor concentrations as compared to the free acid atearly time points. As seen in FIG. 8, intravitreal administration of thesodium salt of Compound 1 resulted in higher aqueous humorconcentrations up tp forty-eight hours post-administration as comparedto the free acid. As seen in FIG. 9, topical ocular administration ofCompound 1 (sodium salt) resulted in increased vitreous humorconcentrations of Compound 1 over time. As seen in FIG. 10, subcutaneousadministration of the sodium salt of Compound 1 resulted in increasedvitreous humor concentrations at 0.5 hr and 1 hr post-dosing as comparedto the free acid. As seen in FIG. 11, intravitreal administration of thesodium salt of Compound 1 resulted in a higher vitreous humorconcentrations at 6 hr post-dosing as compared to the free acid. As seenin FIG. 12, when Compound 1 (sodium salt) was administered via topicalocular administration at 0.7 mg/kg/dose, concentrations were generallyhigher in the cornea as compared to the iris, retina, and choroid. Asseen in FIG. 13, when Compound 1 (sodium salt) was administeredsubcutaneously at 5 mg/kg/dose, concentrations were generally higher inthe iris and choroid as compared to the retina and cornea. As seen inFIG. 14, when Compound 1 (free acid) was administered subcutaneously at5 mg/kg/dose, concentrations were generally higher in the iris andchoroid as compared to the retina and cornea. As seen in FIG. 15, whenCompound 1 (sodium salt) was administered intravitreally at 1.55 mg/kg,concentrations were generally higher in the retina and choroid ascompared to the iris and cornea. As seen in FIG. 16, when Compound 1(free acid) was administered intravitreally at 1.54 mg/kg,concentrations were generally higher in the retina and choroid ascompared to the iris and cornea.

Systemic exposure of Compound 1, as measured in plasma, was confirmed byall routes and formulations. Mean plasma C_(max) was approximately3-fold higher following subcutaneous administration with a Compound 1(sodium salt) solution compared to the subcutaneous administration of aCompound 1 (free acid) suspension, and approximately 2-fold higherfollowing intravitreal administration with Compound 1 (sodium salt)solution compared to the intravitreal administration of a Compound 1(free acid) suspension. Mean plasma AUC_(last) was approximately 2-foldhigher following subcutaneous administration with a Compound 1 (sodiumsalt) solution compared to the subcutaneous administration of a Compound1 (free acid) suspension, whereas mean plasma AUC_(last) was comparablebetween the two dose formulations following intravitreal administration.Mean plasma T_(max) was observed 15 minutes postdose followingsubcutaneous administration with both formulations, 3 and 1 hourspostdose following intravitreal administration with Compound 1 (sodiumsalt) and Compound 1 (free acid), respectively, and 4 hours post dosefollowing ocular administration of Compound 1 (sodium salt).

Ocular tissue concentrations were generally higher from subcutaneous andintravitreal administration with a Compound 1 (sodium salt) solutioncompared to the Compound 1 (free acid) suspension. The rank order ofexposure in aqueous and vitreous humor was intravitreal>>topicalocular>subcutaneous administration. Intravitreal administration of bothtest formulations resulted in higher concentrations in the iris, retina,choroid, and cornea relative to subcutaneous or ocular topicaladministration. The ocular tissue concentrations of Compound 1 in allocular tissues persisted at 72 hours after dosing following intravitrealadministration of both test formulations, with higher concentrationsobserved with the Compound 1 (free acid) suspension formulation relativeto the Compound 1 (sodium salt) solution formulation.

TABLE 5 shows individual and average plasma concentrations (ng/mL) andpharmacokinetic parameters for Compound 1 (sodium salt) after aftertopical ocular administration in male New Zealand White rabbits at 1.2mg/eye (˜0.7 mg/kg/dose) (Group 1).

TABLE 5 Topical; 15% HPβCD + 1% Dextrose in water Time point (hr) Rabbit# Conc. (ng/mL) Average (ng/mL) SD 0.50 1 3.84 3.03 1.15 2 2.21 1.0 31.28 1.46 0.25 4 1.63 2.0 5 0.241 1.14 1.27 6 2.04 4.0 7 13.0 7.48 7.818 1.95 Pharmacokinetic Parameters C_(max) (ng/mL) ± SE 7.48 ± 5.53t_(max) (hr) 4.00 t_(1/2) (hr) ND¹ MRT_(last)(hr) 2.98 AUC_(last) (hr ·ng/mL) ± SE 11.8 ± 5.70 AUC_(∞) (hr · ng/mL) ND¹ Dose Normalized Values²AUC_(last) (hr · kg · ng/mL/mg) 16.8 ± 8.15 AUC_(∞) (hr · kg · ng/mL/mg)ND¹ ND: Not Determined ¹Not determined due to terminal log linear phasenot observed ²Dose normalized by dividing the parameter by the totalnominal dose of 0.7 mg/kg HPβCD: 2-hydroxypropyl-β-cyclodextrin

TABLE 6 shows the individual and average plasma concentrations (ng/mL)and pharmacokinetic parameters for Compound 1 (sodium salt) aftersubcutaneous administration in male New Zealand White Rabbits at 5mg/kg/dose (Group 2).

TABLE 6 Subcutaneous; 15% HPβCD + 1% Dextrose in water (solution) Timepoint (hr) Rabbit # Conc. (ng/mL) Average (ng/mL) SD 0.25 9 1640 1525 163 10 1410 0.50 9 883 1097  302 10 1310 1.0 11 628 646 25.5 12 664 2.013 55.5 180 176 14 305 4.0 15 7.98    7.76 0.32 16 7.53 PharmacokineticParameters C_(max) (ng/mL) ± SE 1525 ± 115 t_(max) (hr) 0.25 t_(1/2)(hr) 0.47 MRT_(last)(hr) 0.87 AUC_(last) (hr · ng/mL) ± SE 1555 ± 195AUC_(∞) (hr · ng/mL) 1560 Dose Normalized Values¹ AUC_(last) (hr · kg ·ng/mL/mg)   311 ± 38.9 AUC_(∞) (hr · kg · ng/mL/mg) 312 ¹Dose normalizedby dividing the parameter by the total nominal dose of 5 mg/kg Datapoints used for half-life determination are in bold.

TABLE 7 shows individual and average plasma concentrations (ng/ml) andpharmacokinetic parameters for Compound 1 (free acid) after subcutaneousadministration in male New Zealand White rabbits at 5 mg/kg/dose (Group3).

TABLE 7 Subcutaneous; 40 mM Phosphate Buffer pH 4.0 + 2.5% Dextrose inwater (suspension) Time point (hr) Rabbit # Conc. (ng/mL) Average(ng/mL) SD 0.25 17 225 395 240 18 565 0.50 17 272 337 91.2 18 401 1.0 19300 295 7.78 20 289 2.0 21 194 206 16.3 22 217 4.0 23 111 110 2.12 24108 Pharmacokinetic Parameters C_(max) (ng/mL) ± SE 395 ± 170 t_(max)(hr) 0.25 t_(1/2) (hr) 2.12 MRT_(last)(hr) 1.58 AUC_(last) (hr · ng/mL)± SE 864 ± 69  AUC_(∞) (hr · ng/mL) 1198 Dose Normalized Values¹AUC_(last) (hr · kg · ng/mL/mg)  173 ± 13.8 AUC_(∞) (hr · kg · ng/mL/mg)240 ¹Dose normalized by dividing the parameter by the total nominal doseof 5 mg/kg Data points used for half-life determination are in bold.

TABLE 8 shows individual and average plasma concentrations (ng/ml) andpharmacokinetic parameters for Compound 1 (sodium salt) afterintravitreal administration in male New Zealand White rabbits at 2.5mg/eye (˜1.55 mg/kg) (Group 4).

TABLE 8 Intravitreal; 10% HPβCD + 2% Dextrose in water (solution) Timepoint (hr) Rabbit # Conc. (ng/mL) Average (ng/mL) SD 1.0 25 33.2 32.31.34 26 31.3 3.0 27 37.5 39.8 3.25 28 42.1 6.0 29 29.3 36.8 10.6 30 44.324.0 31 19.0 16.9 3.04 32 14.7 48.0 25 2.70  2.58 0.18 26 2.45 72.0 270.215  0.27 0.08 28 0.333 Pharmacokinetic Parameters C_(max) (ng/mL) ±SE 39.8 ± 2.30  t_(max) (hr) 3.00 t_(1/2) (hr) 8.08 MRT_(last)(hr) 15.1AUC_(last) (hr · ng/mL) ± SE 953 ± 91.1 AUC_(∞) (hr · ng/mL) 956 DoseNormalized Values¹ AUC_(last) (hr · kg · ng/mL/mg) 615 ± 58.8 AUC_(∞)(hr · kg · ng/mL/mg) 617 ¹Dose normalized by dividing the parameter bythe nominal dose of 1.55 mg/kg Data points used for half-lifedetermination are in bold.

TABLE 9 shows individual and average plasma concentrations (ng/ml) andpharmacokinetic parameters for Compound 1 (free acid) after intravitrealadministration in male New Zealand White rabbits at 2.5 mg/eye (˜1.54mg/kg) (Group 5).

TABLE 9 Intravitreal; 40 mM Phosphate Buffer pH 4.0 + 15% Dextrose(suspension) Time point (hr) Rabbit # Conc. (ng/mL) Average (ng/mL) SD1.0 33 34.6 25.3 13.15 34 16.0 3.0 35 28.4 24.4 5.66 36 20.4 6.0 37 22.023.1 1.48 38 24.1 24.0 39 9.96 12.3 3.35 40 14.7 48.0 33 2.69  3.63 1.3334 4.57 72.0 35 1.83  1.65 0.26 36 1.46 Pharmacokinetic ParametersC_(max) (ng/mL) ± SE 25.3 ± 9.30  t_(max) (hr) 1.00 t_(1/2) (hr) 16.5MRT_(last)(hr) 19.1 AUC_(last) (hr · ng/mL) ± SE 707 ± 53.1 AUC_(∞) (hr· ng/mL) 746 Dose Normalized Values¹ AUC_(last) (hr · kg · ng/mL/mg) 459± 34.5 AUC_(∞) (hr · kg · ng/mL/mg) 484 ¹Dose normalized by dividing theparameter by the nominal dose of 1.54 mg/kg Data points used forhalf-life determination are in bold.

TABLE 10 shows average plasma pharmacokinetic parameters for Compound 1following topical ocular, subcutaneous, and intravitreal administrationin male New Zealand White rabbits.

TABLE 10 PK parameters Topical Subcutaneous Intravitreal ocular Group 12 3 4 5 Salt form Compound 1 Compound 1 Compound 1 Compound 1 Compound 1sodium salt sodium salt free acid sodium salt acid Vehicle 15% 15% 40 mM10% 40 mM HPβCD + HPβCD + Phosphate HPβCD + Phosphate 1% 1% Buffer 2%Bufler Dextrose in Dextrose in pH 4.0 + 2.5% Dextrose in pH 4.0 + waterwater Dextrose in water 2.5% water Dextrose Formulation SolutionSolution Suspension Solution Suspension Dose mg/kg/dose 0.70 5 5 1.551.54 C_(max) (ng/mL) 7.48 1525 395 39.8 25.3 t_(max) (hr) 4.00 0.25 0.253.00 1.00 t_(1/2) (hr) ND 0.47 2.12 8.08 16.5 MRT_(last) (hr) 2.98 0.871.58 15.1 19.1 AUC_(last) (hr · ng/mL) 11.8 1555 864 953 707 AUC_(∞) (hr· ng/mL) ND 1560 1198 956 746 AUC_(last) (hr · kg · ng/mL/mg)¹ 16.8 311173 615 459 AUC_(∞) (hr · kg · ng/mL/mg)¹ ND 312 240 617 484 ¹Dosenormalized by dividing the parameter by the nominal dose in mg/kg ND:Not Determined

TABLE 11 shows individual and average aqueous humor concentrations(ng/g) following topical ocular (Group 1), subcutaneous (Groups 2 and3), and intravitreal (Groups 4 and 5) administration in male New ZealandWhite rabbits.

TABLE 11 Conc. Average Time Animal (ng/mL) Conc¹. SD Group # (hr) ID ODOS (ng/g) (ng/g) Group 1 0.5 1 3.44 1.78 45.8 79.6 2 12.8

1.0 3 4.03 3.55 15.0 22.8 4 3.05

2.0 5 2.46 14.5 31.6 41.7 6

15.8 4.0 7 5.48 5.61 8.24 4.04 8 7.78 14.1 Group 2 0.5 9 23.5 24.6 26.18.58 10 18.0 38.2 1.0 11 4.51 1.84 3.30 1.11 12 3.22 3.63 2.0 13 0.5810.498 0.72 0.42 14 0.453

4.0 15 BLOQ BLOQ ND ND 16 BLOQ BLOQ Group 3 0.5 17 BLOQ BLOQ 1.21 ND 180.519 1.90 1.0 19 0.485 0.684 0.41 0.21 20 0.229 0.257 2.0 21 0.601 BLOQ0.66 0.10 22

0.594 4.0 23 0.209 0.229 0.51 0.50 24 BLOQ

Group 4 6.0 29 90600 77100 80575 6881 30 75300 79300 24 31 4700 51909000 6926 32

6810 48 25 2040 1510 1963 340 26 2330 1970 72 27 23.2 16.1 34.5 17.4 2849.7 49.0 Group 5 6.0 37 34200 15700 26400 8547 38 23400 32300 24 393890 6480 4270 2327 40 5540 1170 48 33 476 632 915 424 34 1220 1330 7235 145 172 120 46.5 36 94.1 70.2 ¹Aqueous humor sample density of 1 g/mLis assumed BLOQ: Below the limit of quantitation (0.2 ng/mL) ND: NotDetermined Bold and italicized values are outliers based on Grubb'soutlier test

TABLE 12 shows individual and average vitreous humor concentrations(ng/g) following topical ocular (Group 1), subcutaneous (Groups 2 and3), and intravitreal (Groups 4 and 5) administration in male New ZealandWhite rabbits.

TABLE 13 shows individual and average iris, retina, choroid, and corneatissue concentrations (ng/g) for Compound 1 (sodium salt) after topicalocular administration in male New Zealand White rabbits at 1.2 mg/eye(˜0.7 mg/kg/dose) (Group 1).

TABLE 14 shows individual and average iris, retina, choroid, and corneatissue concentrations (ng/g) for Compound 1 (sodium salt) aftersubcutaneous administration in male New Zealand White rabbits at 5mg/kg/dose (Group 2).

TABLE 15 shows individual and average iris, retina, choroid, and corneatissue concentrations (ng/g) for Compound 1 (free acid) aftersubcutaneous administration in male New Zealand White rabbits at 5mg/kg/dose (Group 3).

TABLE 16 shows individual and average iris, retina, choroid, and corneatissue concentrations (ng/g) for Compound 1 (free acid) aftersubcutaneous administration in male New Zealand White rabbits at 5mg/kg/dose (Group 3).

TABLE 17 shows individual and average iris, retina, choroid, and corneatissue concentrations (ng/g) for Compound 1 (sodium salt) afterintravitreal administration in male New Zealand White rabbits at 2.5mg/eye (˜1.55 mg/kg) (Group 4).

TABLE 18 shows individual and average iris, retina, choroid, and corneatissue concentrations (ng/g) for Compound 1 (free acid) afterintravitreal administration in male New Zealand White rabbits at 2.5mg/eye (˜1.54 mg/kg) (group 5).

TABLE 19 shows average ocular tissue peak concentrations for Compound 1following topical ocular, subcutaneous and intravitreal administrationin male New Zealand White rabbits.

TABLE 12 Conc. Average Time Animal (ng/mL) Conc¹. SD Group # (hr) ID ODOS (ng/g) (ng/g) Group 1 0.5 1

0.528 0.61 0.17 2 0.549 0.507 1.0 3 1.97 0.282 2.09 1.32 4 3.28 2.83 2.05 1.14

3.33 4.51 6 1.14 0.950 4.0 7 1.09 2.20 4.01 5.50 8 0.551

Group 2 0.5 9 0.77 1.03 0.83 0.23 10 0.537 0.981 1.0 11 0.252 0.766 0.450.23 12 0.442 0.337 2.0 13 BLOQ BLOQ ND ND 14 BLOQ BLOQ 4.0 15 BLOQ BLOQND ND 16 BLOQ BLOQ Group 3 0.5 17 BLOQ 0.227 0.40 0.27 18 0.261

1.0 19 0.407 BLOQ 0.41 ND 20 BLOQ BLOQ 2.0 21 BLOQ BLOQ ND ND 22 BLOQBLOQ 4.0 23 BLOQ 0.408 0.41 ND 24 BLOQ BLOQ Group 4 6.0 29 1450000592000 988500 554214 30 1480000 432000 24 31 438000 295000 349500 8599432 406000 259000 48 25 85200 82300 82000 9796 26 68600 91900 72 27 1450013500 13450 1237 28 11700 14100 Group 5 6.0 37 592000 625000 479750163272 38 432000 270000 24 39 296000 528000 408750 117721 40 491000320000 48 33 75900 148000 97800 35923 34 68300 99000 72 35 96500 10100065350 40696 36 16200 47700 ¹Vitreous humor sample density of 1 g/mL isassumed BLOQ: Below the limit of quantitation (0.2 ng/mL) ND: NotDetermined; bold and italicized values are outliers based on Grubb'soutlier test

TABLE 13 Conc. Tissue Homogenate Conc¹. Time Animal (ng/mL) Weight (g)Vol. (mL) (ng/g) Average SD Tissue (hr) ID OD OS OD OS OD OS OD OS(ng/g) (ng/g) Iris 0.5 1 2.55 1.62 0.025 0.024 0.28 0.26 28.1 17.8 24.37.16 2 1.7 2.95 0.024 0.032 0.26 0.35 18.7 32.5 1 3 1.57 2.70 0.0240.016 0.26 0.17 17.3 29.7 55.2 41.9 4 5.69 10.1 0.025 0.033 0.27 0.3662.6 111 2 5 1.12 2.99 0.022 0.024 0.24 0.27 12.3 32.9 51.9 39.2 6 5.409.38 0.034 0.032 0.38 0.35 59.4 103 4 7 2.97 2.79 0.020 0.027 0.22 0.3032.7 30.7 261 462 8 2.54 86.7 0.031 0.024 0.34 0.27 27.9

Retina 0.5 1 0.695 3.06 0.053 0.031 0.59 0.34 7.65 33.7 25.6 12.2 2 2.543.01 0.029 0.051 0.32 0.56 27.9 33.1 1 3 6.99 2.01 0.035 0.042 0.39 0.4776.9 22.1 59.2 28.6 4 7.81 4.70 0.034 0.063 0.37 0.69 85.9 51.7 2 5 1.568.93 0.044 0.037 0.48 0.40 17.2 98.2 48.3 36.0 6 4.54 2.54 0.069 0.0470.76 0.52 49.9 27.9 4 7 1.60 5.89 0.046 0.059 0.50 0.65 17.6 64.8 405684 8 9.88 130 0.054 0.045 0.59 0.49 109

Choroid 0.5 1 2.75 1.47 0.034 0.044 0.37 0.48 30.3 16.2 57.7 47.5 2 5.5511.2 0.051 0.043 0.57 0.47 61.1 123 1 3 5.56 1.50 0.050 0.047 0.55 0.5261.2 16.5 32.2 20.4 4 2.89 1.77 0.037 0.067 0.40 0.74 31.8 19.5 2 5 1.193.99 0.050 0.060 0.55 0.66 13.1 43.9 59.2 43.0 6 10.5 5.86 0.054 0.0270.59 0.30 116 64.5 4 7 2.53 7.37 0.039 0.034 0.43 0.38 27.8 81.1 165 2248 4.74 45.4 0.036 0.035 0.39 0.38 52.1

Cornea 0.5 1 21.8 38.8 0.079 0.073 0.87 0.81 240 427 1015 1342 2 33.6275 0.066 0.068 0.73 0.75 370

1 3 87.2 43.8 0.068 0.076 0.74 0.83 959 482 548 307 4 19.9 48.4 0.0650.067 0.72 0.73 219 532 2 5 20.9 25.4 0.070 0.073 0.77 0.81 230 279 10731210 6 87.8 256 0.068 0.073 0.75 0.81 966 2816 4 7 44.8 37.0 0.084 0.0810.93 0.90 493 407 534 233 8 32.9 79.4 0.075 0.074 0.83 0.82 362 873¹Tissue sample density 1 g/mL is assumed; BLOQ: Below the limit ofquantitation (0.5 ng/mL); ND: Not Determined; bold and italicized valuesare outliers based on Grubb's outlier test.

TABLE 14 Conc. Tissue Homogenate Conc¹. Time Animal (ng/mL) Weight (g)Vol. (mL) (ng/g) Average SD Tissue (hr) ID OD OS OD OS OD OS OD OS(ng/g) (ng/g) Iris 0.5 9 27.7 29.2 0.020 0.028 0.22 0.31 305 321 459 20910 41.3 68.8 0.029 0.026 0.32 0.29 454 757 1 11 11.4 8.87 0.020 0.0220.21 0.24 125 97.6 94.7 28.5 12 9.02 5.13 0.026 0.036 0.28 0.40 99.256.4 2 13 4.76 3.07 0.018 0.022 0.19 0.25 52.4 33.8 29.7 17.4 14 1.791.18 0.019 0.023 0.21 0.26 19.7 13.0 4 15 2.12 BLOQ 0.020 0.021 0.220.23

ND 30.4 6.13 16 3.07 3.10 0.017 0.030 0.18 0.33 33.8 34.1 Retina 0.5 92.77 4.36 0.038 0.040 0.41 0.44 30.5 48.0 40.5 9.23 10 3.17 4.43 0.0490.059 0.54 0.65 34.9 48.7 1 11 2.04 3.93 0.043 0.064 0.48 0.70 22.4 43.232.6 14.3 12 1.66 4.22 0.040 0.059 0.44 0.65 18.3 46.4 2 13 1.36 1.620.046 0.062 0.50 0.68 15.0 17.8 16.4 ND 14 BLOQ BLOQ 0.048 0.077 0.530.85 ND ND 4 15 BLOQ BLOQ 0.061 0.059 0.67 0.65 ND ND 19.7 ND 16 1.79BLOQ 0.037 0.049 0.41 0.54 19.7 ND Choroid 0.5 9 24.0 25.6 0.030 0.0370.33 0.40 264 282 266 21.8 10 25.6 21.4 0.027 0.029 0.30 0.31 282 235 111 29.1 13.1 0.047 0.057 0.51 0.63 320 144 200 88 12 19.2 11.4 0.0340.066 0.38 0.72 211 125 2 13 13.5 7.03 0.039 0.040 0.43 0.44 149 77.368.8 58.7 14 2.32 2.15 0.022 0.047 0.24 0.52 25.5 23.7 4 15 1.70 1.220.040 0.037 0.44 0.41 18.7 13.4 15.5 2.58 16 1.50 1.22 0.048 0.040 0.530.44 16.5 13.4 Cornea 0.5 9 0.883 2.46 0.062 0.065 0.68 0.71 9.71 27.119.4 7.22 10 1.77 1.94 0.068 0.063 0.75 0.69 19.5 21.3 1 11 2.37 4.520.063 0.065 0.69 0.72 26.1

31.1 12.4 12 2.13 2.30 0.074 0.073 0.81 0.80 23.4 25.3 2 13 1.06 0.9980.063 0.073 0.69 0.80 11.7 11.0 9.45 3.26 14 0.518 BLOQ 0.070 0.064 0.770.70

ND 4 15 0.752 0.784 0.064 0.064 0.70 0.71 8.27 8.62 10.1 2.58 16 0.8731.26 0.070 0.074 0.77 0.81 9.60 13.9 ¹Tissue sample density of 1 g/mL isassumed BLOQ: Below the limit of quantitation (0.5 ng/mL) ND: NotDetermined; bold and italicized values are outliers based on Grubb'soutlier test

TABLE 15 Conc. Tissue Homogenate Conc¹. Time Animal (ng/mL) Weight (g)Vol. (mL) (ng/g) Average SD Tissue (hr) ID OD OS OD OS OD OS OD OS(ng/g) (ng/g) Iris 0.5 17 7.1 4.27 0.032 0.017 0.36 0.19 78.1 47.0 50.319.0 18 3.39 3.54 0.041 0.024 0.45 0.26 37.3 38.9 1 19 4.35 4.33 0.0450.020 0.49 0.22 47.9 47.6 58.0 30.1 20 9.29 3.12 0.034 0.018 0.38 0.19102 34.3 2 21 2.77 2.68 0.033 0.017 0.37 0.19 30.5 29.5 27.6 6.23 222.91 1.67 0.044 0.023 0.48 0.25 32.0

4 23 2.41 1.54 0.015 0.077 0.17 0.85 26.5 16.9 17.5 7.27 24 1.63 0.7940.028 0.041 0.30 0.46 17.9 8.73 Retina 0.5 17 6.72 3.33 0.030 0.053 0.330.58 73.9 36.6 38.7 25.6 18 2.87 1.16 0.030 0.074 0.33 0.81 31.6 12.8 119 0.942 0.63 0.035 0.071 0.38 0.79 10.4 6.93 10.2 3.19 20 BLOQ 1.210.042 0.047 0.47 0.52 ND 13.3 2 21 0.574 0.63 0.050 0.046 0.56 0.51 6.316.93 10.5 6.73 22 BLOQ 1.66 0.028 0.043 0.30 0.47 ND

4 23 BLOQ 1.18 0.043 0.044 0.47 0.48 ND 13.0 35.3 ND 24 BLOQ 5.24 0.0460.072 0.51 0.80 ND 57.6 Choroid 0.5 17 7.83 7.55 0.020 0.029 0.22 0.3286.1 83.1 127 50.2 18 16.7 14.0 0.024 0.054 0.27 0.59 184 154 1 19 6.048.01 0.036 0.042 0.40 0.46 66.4 88.1 83.3 12.2 20 8.65 7.60 0.033 0.0360.37 0.40 95.2 83.6 2 21 3.32 4.84 0.036 0.034 0.39 0.37 36.5 53.2 47.78.17 22 4.26 4.94 0.046 0.031 0.50 0.34 46.9 54.3 4 23 4.82 2.12 0.0300.023 0.33 0.25 53.0 23.3 61.0 39.5 24 4.65 10.6 0.034 0.078 0.37 0.8551.2 117 Cornea 0.5 17 BLOQ BLOQ 0.064 0.063 0.70 0.70 ND ND 7.96 ND 180.55 0.897 0.077 0.066 0.84 0.72 6.05 9.87 1 19 BLOQ BLOQ 0.065 0.0580.72 0.64 ND ND 12.2 ND 20 1.11 BLOQ 0.065 0.067 0.72 0.74 12.2 ND 2 210.514 BLOQ 0.073 0.066 0.80 0.73 5.65 ND 5.65 ND 22 BLOQ BLOQ 0.0760.065 0.84 0.72 ND ND 4 23 0.942 BLOQ 0.066 0.011 0.72 0.12 10.4 ND 15.810.3 24 0.847 2.51 0.068 0.062 0.75 0.68 9.32

¹Tissue sample density of 1 g/mL is assumed BLOQ: Below the limit ofquantitation (0.5 ng/mL) ND: Not Determined; bold and italicized valuesare outliers based on Grubb's outlier test

TABLE 16 Conc. Tissue Homogenate Conc¹. Time Animal (ng/mL) Weight (g)Vol. (mL) (ng/g) Average SD Tissue (hr) ID OD OS OD OS OD OS OD OS(ng/g) (ng/g) Iris 0.5 17 7.1 4.27 0.032 0.017 0.36 0.19 78.1 47.0 50.319.0 18 3.39 3.54 0.041 0.024 0.45 0.26 37.3 38.9 1 19 4.35 4.33 0.0450.020 0.49 0.22 47.9 47.6 58.0 30.1 20 9.29 3.12 0.034 0.018 0.38 0.19102 34.3 2 21 2.77 2.68 0.033 0.017 0.37 0.19 30.5 29.5 27.6 6.23 222.91 1.67 0.044 0.023 0.48 0.25 32.0

4 23 2.41 1.54 0.015 0.077 0.17 0.85 26.5 16.9 17.5 7.27 24 1.63 0.7940.028 0.041 0.30 0.46 17.9 8.73 Retina 0.5 17 6.72 3.33 0.030 0.053 0.330.58 73.9 36.6 38.7 25.6 18 2.87 1.16 0.030 0.074 0.33 0.81 31.6 12.8 119 0.942 0.63 0.035 0.071 0.38 0.79 10.4 6.93 10.2 3.19 20 BLOQ 1.210.042 0.047 0.47 0.52 ND 13.3 2 21 0.574 0.63 0.050 0.046 0.56 0.51 6.316.93 10.5 6.73 22 BLOQ 1.66 0.028 0.043 0.30 0.47 ND

4 23 BLOQ 1.18 0.043 0.044 0.47 0.48 ND 13.0 35.3 ND 24 BLOQ 5.24 0.0460.072 0.51 0.80 ND 57.6 Choroid 0.5 17 7.83 7.55 0.020 0.029 0.22 0.3286.1 83.1 127 50.2 18 16.7 14.0 0.024 0.054 0.27 0.59 184 154 1 19 6.048.01 0.036 0.042 0.40 0.46 66.4 88.1 83.3 12.2 20 8.65 7.60 0.033 0.0360.37 0.40 95.2 83.6 2 21 3.32 4.84 0.036 0.034 0.39 0.37 36.5 53.2 47.78.17 22 4.26 4.94 0.046 0.031 0.50 0.34 46.9 54.3 4 23 4.82 2.12 0.0300.023 0.33 0.25 53.0 23.3 61.0 39.5 24 4.65 10.6 0.034 0.078 0.37 0.8551.2 117 Cornea 0.5 17 BLOQ BLOQ 0.064 0.063 0.70 0.70 ND ND 7.96 ND 180.55 0.897 0.077 0.066 0.84 0.72 6.05 9.87 1 19 BLOQ BLOQ 0.065 0.0580.72 0.64 ND ND 12.2 ND 20 1.11 BLOQ 0.065 0.067 0.72 0.74 12.2 ND 2 210.514 BLOQ 0.073 0.066 0.80 0.73 5.65 ND 5.65 ND 22 BLOQ BLOQ 0.0760.065 0.84 0.72 ND ND 4 23 0.942 BLOQ 0.066 0.011 0.72 0.12 10.4 ND 15.810.3 24 0.847 2.51 0.068 0.062 0.75 0.68 9.32

¹Tissues ample density of 1 g/mL is assumed BLOQ: Below the limit ofquantitation (0.5 ng/mL) ND: Not Determined; bold and italicized valuesare outliers based on Grubb's outlier test

TABLE 17 Conc. Tissue Homogenate Conc¹. Time Animal (ng/mL) Weight (g)Vol. (mL) (ng/g) Avg. SD Tissue (hr) ID OD OS OD OS OD OS OD OS (ng/g)(ng/g) Iris 6.0 29 35500 34000 0.027 0.017 0.29 0.19 390500 374000351725 38024 30 27800 30600 0.023 0.022 0.25 0.24 305800 336600 24 316890 7610 0.044 0.047 0.48 0.52 75790 83710 141350 97709 32 11000 259000.030 0.035 0.33 0.39 121000 284900 48 25 2380 1960 0.025 0.035 0.270.39 26180 21560 24585 4778 26 1820 2780 0.027 0.028 0.30 0.31 2002030580 72 27 169 225 0.027 0.024 0.30 0.26 1859 2475 1550 789 28 110 59.50.025 0.025 0.28 0.27 1210 655 Retina 6.0 29 39200 41100 0.043 0.0530.47 0.58 431200 452100 774400 418169 30 119000 82300 0.042 0.040 0.460.44 1309000 905300 24 31 29200 28000 0.052 0.041 0.57 0.45 321200308000 355850 48612 32 35200 3700 0.059 0.078 0.65 0.86 387200 407000 4825 6490 6030 0.058 0.048 0.63 0.53 71390 66330 72628 6090 26 7360 65300.055 0.081 0.60 0.89 80960 71830 72 27 750 370 0.048 0.046 0.52 0.508250 4070 6056 1786 28 598 484 0.042 0.053 0.46 0.58 6578 5324 Choroid6.0 29 164000 105000 0.031 0.031 0.34 0.34 1804000 1155000 947375 67148630 31500 44000 0.035 0.049 0.38 0.54 346500 484000 24 31 11800 98900.034 0.030 0.37 0.33 129800 108790 138848 43289 32 18400 10400 0.0320.027 0.36 0.30 202400 114400 48 25 3480 3740 0.038 0.037 0.41 0.4138280 41140 38638 5866 26 4040 2790 0.059 0.054 0.65 0.59 44440 30690 7227 107 282 0.028 0.050 0.31 0.55 1177 3102 2723 1039 28 311 290 0.0280.040 0.30 0.44 3421 3190 Cornea 6.0 29 6300 6940 0.062 0.060 0.68 0.6669300 76340 71445 4484 30 6710 6030 0.078 0.080 0.86 0.88 73810 66330 2431 2180 1560 0.073 0.082 0.80 0.90 23980 17160 23678 6419 32 2940 19300.075 0.083 0.82 0.91 32340 21230 48 25 1050 662 0.071 0.070 0.78 0.7711550 7282 7527 2801 26 538 487 0.072 0.076 0.79 0.83 5918 5357 72 2718.0 20.1 0.068 0.065 0.75 0.71 198 221 421 244 28 56.9 58.1 0.066 0.0700.72 0.77 626 639 ¹Tissue sample density of 1 g/mL is assumed BLOQ:Below the limit of quantitation (0.5 ng/mL) ND: Not Determined; bold anditalicized values are outliers based on Grubb's outlier test

TABLE 18 Conc. Tissue Homogenate Conc¹. Time Animal (ng/mL) Weight (g)Vol. (mL) (ng/g) Avg. SD Tissue (hr) ID OD OS OD OS OD OS OD OS (ng/g)(ng/g) Iris 6.0 37 18500 13800 0.028 0.027 0.30 0.29 203500 151800210650 99417 38 32100 12200 0.024 0.029 0.27 0.32 353100 134200 24 397670 14100 0.028 0.032 0.30 0.36 84370 155100 112668 32535 40 11000 82000.033 0.031 0.36 0.34 121000 90200 48 33 1010 1950 0.035 0.029 0.39 0.3211110 21450 16775 5934 34 1110 2030 0.023 0.029 0.25 0.32 12210 22330 7235 279 1800 0.031 0.038 0.34 0.42 3069 19800 10313 8202 36 351 13200.033 0.031 0.36 0.34 3861 14520 Retina 6.0 37 146000 154000 0.060 0.0410.66 0.45 1606000 1694000 1988250 910606 38 303000 120000 0.107 0.0451.18 0.50

 

1320000 24 39 130000 98900 0.068 0.063 0.75 0.70 1430000 1087900 1572725455441 40 145000 198000 0.077 0.078 0.84 0.85 1595000 2178000 48 3366700 14000 0.053 0.045 0.58 0.50 733700 154000 679800 394530 34 65500101000 0.068 0.068 0.74 0.74 720500 1111000 72 35 9890 10800 0.047 0.0480.52 0.52 108790 118800 109065 31421 36 6070 12900 0.056 0.055 0.62 0.6166770 141900 Choroid 6.0 37 32800 63400 0.061 0.042 0.67 0.46 360800697400 663575 208925 38 75400 69700 0.096 0.066 1.05 0.73 829400 76670024 39 15200 28400 0.017 0.032 0.19 0.35 167200 312400 397650 201714 4057500 43500 0.042 0.044 0.46 0.48 632500 478500 48 33 9940 9320 0.0470.044 0.51 0.48 109340 102520 120010 28663 34 9580 14800 0.042 0.0310.46 0.34 105380

72 35 2180 2660 0.039 0.035 0.43 0.39 23980 29260 27555 3751 36 22702910 0.041 0.036 0.45 0.40 24970 32010 Cornea 6.0 37 7910 3140 0.0630.063 0.69 0.69 87010 34540 54560 36663 38 7610 1180 0.055 0.053 0.600.58 83710 12980 24 39 1520 1190 0.069 0.075 0.76 0.83 16720 13090 172707296 40 2520 1050 0.085 0.081 0.93 0.89 27720 11550 48 33 437 293 0.0720.077 0.80 0.85 4807 3223 4634 1278 34 384 571 0.073 0.073 0.80 0.804224 6281 72 35 37.7 117 0.085 0.076 0.93 0.83 415 1287 762 397 36 77.245.3 0.069 0.067 0.76 0.74 849 498 ¹Tissue sample density of 1 g/mL isassumed BLOQ: Below the limit of quantitation (0.5 ng/mL) ND: NotDetermined; bold and italicized values are outliers based on Grubb'soutlier test.

TABLE 19 Dose Route Topical Subcutaneous Intravitreal ocular Group 1 2 34 5 Salt form Compound Compound Compound Compound Compound 1 sodium 1sodium 1 free acid 1 sodium 1 free acid salt salt salt Vehicle 15% 15%40 mM 10% 40 mM HPβCD + HPβCD + Phosphate HPβCD + Phosphate 1% 1% Buffer2% Buffer Dextrose Dextrose pH 4.0 + Dextrose pH 4.0 + in water in water2.5% in water 2.5% Dextrose Dextrose in water Formulation SolutionSolution Suspension Solution Suspension Dose 0.70 5 5 1.55 1.54(mg/kg/dose) Tissue Average Peak Concentration (ng/g) Aqueous 45.8 26.11.21 80575 26400 Humor Vitreous 0.61 0.83 0.40 988500 479750 Humor Iris24.3 459 50.3 351725 210650 Retina 25.6 40.5 38.7 774400 1988250 Choroid57.7 266 127 947375 663575 Cornea 1015 19.4 7.96 71445 54560

Example 3 Tolerability and Effect on Intraocular Pressure of Compound 1(Sodium Salt) Following Repeated Topical and Subcutaneous Administration

To measure the tolerability and effect of Compound 1 (sodium salt) onintraocular pressure following repeated topical and subcutaneousadministration, normotensive New Zealand White rabbits were treated withCompound 1 (sodium salt).

Prior to treatment initiation, selection of animals for the study wasbased on a visual appraisal of good clinical condition and body weightspecifications. All animals were healthy at the time of animalselection. Animals selected for use in this study were as uniform in ageand weight as possible. The animals were housed in individual cageswithin the same room during the study. No other species were housed inthe same room. The room was well ventilated (greater than 10 air changesper hour) with at least 60% fresh air. A 12-hour light/12-hour darkphotoperiod was maintained, except when rooms were illuminated duringthe dark cycle to accommodate necessary study procedures. Animals had adlibitum access to species specific chow. Chlorinated, municipal tapwater was made available ad libitum to each animal via water bottles.All study animals were acclimated to their designated housing for 16days prior to study start. All animals were weighed prior to the startof the procedures and ranged from 2.88 to 3.44 kilograms at study start.

Vehicle 1 (15% HPβCD, 1% Dextrose) was prepared by introducing 15 g ofHPβCD into a glass container, adding 80 mL of deionized water to thecontainer, and mixing the contents by vortex until the HPβCD powder wasfully dissolved. 2 mL of 50% dextrose solution was then added to thecontainer, the volume was brought to 100 mL with deionized water tocreate a 15% HPβCD and 1% dextrose solution, and the contents were mixedby vortex. The resulting solution was sterile filtered through a 0.2 μmfilter into 14 separate sterile bottles of sufficient volume for dailyvehicle control dosing and preparation of Compound 1 dosing solutions,and stored refrigerated at 2-8° C.

A first batch of Vehicle 2 (15% HPβCD, 2% Dextrose) was prepared byintroducing 1.5 g of HPβCD into a glass container, adding 8 mL ofdeionized water to the container, and mixing by vortex the contentsuntil the HPβCD powder was fully dissolved. 0.4 mL of 50% dextrosesolution was then added to the container, the volume was brought up to10 mL with deionized water to create a 15% HPβCD and 2% dextrosesolution, and the contents were mixed by vortex. The resulting solutionwas sterile filtered through a 0.2 μm filter into a sterile bottle andstored refrigerated at 2-8° C.

A second batch of Vehicle 2 (15% HPβCD, 2% Dextrose), was prepared byintroducing 0.75 g of HPβCD into a glass container, adding 4 mL ofdeionized water to the container, and mixing by vortex the contentsuntil the HPβCD powder was fully dissolved. 0.2 mL of 50% dextrosesolution was then added to the container, the volume was brought to 5 mLwith deionized water to create a 15% HPβCD and 2% dextrose solution, andthe contents were mixed by vortex. The resulting solution was sterilefiltered through a 0.2 μm filter into a sterile bottle and storedrefrigerated at 2-8° C. Compound 1 (sodium salt) dosing solutions wereprepared fresh once daily for each day of dosing.

A 15 mg/mL Compound 1 (sodium salt) solution was prepared by introducingCompound 1 (sodium salt) into glass containers, adding Vehicle 2 at avolume to create a 15 mg/mL Compound 1 (sodium salt) solution, andmixing by vortex and/or sonicating the contents until the Compound 1(sodium salt) powder was fully dissolved and a clear solution wasformed. The pH was confirmed to be between 6.5-7 using pH indicatorstrips. The solution was then sterile filtered through a 0.2 μm filterinto a sterile bottle and stored refrigerated at 2-8° C.

A 40 mg/mL Compound 1 (sodium salt) solution was prepared by introducingCompound 1 (sodium salt) into glass containers pre-calibrated to ˜95% ofthe final formulation volume, then adding Vehicle 1 to reach ˜90% of thefinal formulation volume, and mixing by vortex and/or sonicating thecontents until the Compound 1 (sodium salt) powder was fully dissolvedand a clear solution was formed. The volume was brought to thecalibration mark and then to the final formulation volume withadditional Vehicle 1 to create a 40 mg/mL Compound 1 (sodium salt)solution. If necessary, the solution was further sonicated. The pH wasconfirmed to be between 7-7.5 using pH indicator strips. The solutionwas sterile filtered through a 0.2 μm filter into a sterile bottle andstored refrigerated at 2-8° C.

All dosing solutions were allowed to come to room temperature beforedosing. A 0.2 mL aliquot of each formulation was collected prior todosing each day, snap frozen on dry ice, and stored frozen at −60 to−80° C. for potential future analysis.

Prior to placement on study, each animal underwent an ophthalmicexamination (slitlamp biomicroscopy and indirect ophthalmoscopy). Ocularfindings were scored according to a modified McDonald-Shadduck ScoringSystem and recorded on a standardized data sheet. The acceptancecriteria for placement on study were scores of “0” for all variables.

Animals were acclimated 1 to 2 times per day to the intraocular pressure(IOP) measurement procedures prior to initiation of the study todetermine baseline IOP levels. IOP acclimation was performed in the twoweeks prior to study start for a total of 5 days. Animals withunacceptable IOP values were excluded from the study. Prior to takingall IOP measurements, 1 to 2 drops of a 0.5% proparacaine solution wereapplied to the eye as a topical anesthetic. OP measurements wereperformed with a pneumotonometer.

Test and control formulations were administered to the animals once ortwice daily topically into both eyes or subcutaneously starting on Day 1according to TABLE 20 and TABLE 21 below. PM dosing, where applicable,was performed ˜8 hours after AM dosing.

TABLE 20 Compound 1 (sodium salt) Group Treatment Dose Vehicle Doseroute concentration 1 Vehicle 1 N/A 15% Topical N/A HPβCD, BID  1% for 7days Dextrose (OU) 2 Compound 0.45 mg/eye 15% Topical 15 mg/mL 1 HPβCD,BID (sodium  2% for 7 days salt) Dextrose (OU) 3 Compound 1.2 mg/eye 15%Topical 40 mg/mL 1 HPβCD, BID (sodium  1% for 7 days salt) Dextrose (OU)4 Compound 1.2 mg/eye 15% Topical 40 mg/mL 1 HPβCD, QD (sodium  1% for 7days salt) Dextrose (OU) 5 Compound 10 mg/kg 15% SC BID 40 mg/mL 1HPβCD, for 7 days (sodium  1% salt) Dextrose OU: both eyes BID: twicedaily (BID dose groups received only AM dosing on Day 7) QD: once dailyHPβCD: Hydroxy Propyl Beta Cyclodextrin

TABLE 21 Clinical Intraocular ophthalmic pressure Dose examination timemeasurement Group N Volume points time points 1 5 30 μL/eye Baseline(prior to Acclimation, 2 5 30 μL/eye first dose) and baseline (prior to3 5 30 μL/eye Days 1, 4, and 8 first dose) 4 5 30 μL/eye AM/PM, Day 1 55 0.25 mL/kg AM/PM, Day 2 AM, Day 3 AM, Day 4 AM, Day 5 AM, Day 6 AM,Day 7 AM/PM, Day 8

Animals were observed within their cages once daily throughout the studyperiod. Each animal was observed for changes in general appearance andbehavior, and was weighed prior to the study initiation. General healthobservations were recorded daily beginning on Day 1 and continuingthroughout the course of the study.

Ophthalmic examination (slit-lamp biomicroscopy only) was performed atbaseline (prior to the start of dosing) and on Days 1, 4, and 8. Ocularfindings were scored according to a modified McDonald-Shadduck ScoringSystem. A slit lamp was used to observe conjunctival discharge,conjunctival congestion, conjunctival congestion, the cornea, thesurface area of cornea involvement, pannus, pupillary response, aqueousflare, cellular flare, iris involvement, and the lens. An indirectophthalmoscope was used to observe the vitreous, vitral hemorrhage,retinal detachment, retinal hemorrhage, and choroidal/retinalinflammation. Animals were prepared for observation by using a solution(atropine, tropicaminde, or phenylephrine) to dilate the pupils.

Conjunctival discharge was defined as a whitish gray precipitate fromthe eye. Scoring was as follows.

-   0=Normal, no discharge.-   1=Discharge above normal and present on the inner portion of the eye    but not on the lids or hairs of the eyelids.-   2=Discharge is abundant, easily observed and has collected on the    lids and hairs of the eyelids.-   3=Discharge has been flowing over the eyelids so as to wet the hairs    substantially on the skin around the eye.

Conjunctival congestion causes the blood vessels of the eye to becomeenlarged. Scoring was as follows.

-   0=Normal, may appear blanched to reddish pink without perilimbal    injection (except at the 12:00 and 6:00 positions) with vessels of    the palpebral and bulbar conjunctiva easily observed.-   1=A flushed, reddish color predominantly confined to the palpebral    conjunctiva with some perilimbal injection but primarily confined to    the lower and upper parts of the eye from the 4:00 to the 7:00 and    11:00 to 1:00 positions.-   2=Bright red color of the palpebral conjunctiva with accompanying    perilimbal injection covering at least 75% of the circumference of    the perilimbal region.-   3=Dark, beefy red color with congestion of both the bulbar and    palpebral conjunctiva along with pronounced perilimbal injection and    the presence of petechial on the conjunctiva. The petechial    generally predominates along the nictitating membrane and upper    palprebal conjunctiva.

Conjunctival swelling, defined as swelling of the conjunctiva, wasscored as follows.

-   0=Normal or no swelling of the conjunctival tissue.-   1=Swelling above normal without eversion of the eyelids (easily    discerned by noting upper and lower eyelids are positioned as in the    normal eye); swelling generally starts in the lower cul-de-sac near    the inner canthus.-   2=Swelling with misalignment of the normal approximation of the    lower and upper eyelids; primarily confined to the upper eyelid so    that in the initial stages, the misapproximation of the eyelids    begins by partial eversion of the upper eyelid. In this state the    swelling is confined generally to the upper eyelid with some    swelling in the lower cul-de-sac.-   3=Swelling definite with partial eversion of the upper and lower    eyelids essentially equivalent. This can be easily observed by    looking at the animal head-on and noting the position of the    eyelids; if the eye margins do not meet, eversion has occurred.-   4=Eversion of the upper eyelid is pronounced with less pronounced    eversion of the lower eyelid. It is difficult to retract the lids    and observe the perilimbal region.

Iris involvement was observed by checking the iris for hyperemia of theblood vessels. Scoring was as follows.

-   0=Normal iris without any hyperemia of the blood vessels.-   1=Some loss of transparency. Only the epithelium and/or the anterior    half of the stroma are involved. The underlying structures are    clearly visible although some cloudiness may be readily apparent.-   2=Involvement of the entire thickness of the stroma. With diffuse    illumination, the underlying structures are just barely visible (can    still observe flare, iris, pupil response, and lens).-   3=Involvement of the entire thickness of the stroma. With diffuse    illumination, the underlying structures cannot be seen.

The surface area of cornea involvement was observed by checking the eyefor cloudiness in the stromal region. Scoring was as follows.

-   0=Normal.-   1=1-25% area of stromal cloudiness.-   2=26-50% area of stromal cloudiness.-   3=51-75% area of stromal cloudiness.-   4=76-100% area of stromal cloudiness.

Pannus was observed by checking for vascularization of the cornea.Scoring was as follows.

-   0=No pannus (vascularization of the cornea).-   1=Vascularization present but vessels have not invaded the entire    cornea circumference.-   2=Vessels have invaded 2 mm or more around entire corneal surface.

Pupillary response was observed by checking for any blockage or asluggish response in the pupillary region. Scoring was as follows.

-   0=Normal pupil response.-   1=Sluggish or incomplete pupil response.-   2=No pupil response.-   3=No pupil response due to pharmacological blockage.

Aqueous flare was observed through the breakdown of the blood-aqueousbarrier. Scoring was as follows.

-   0=None.-   1=1+.-   2=2+.-   3=3+.-   4=4+ (fibrin).

Cellular flare was observed through cellular observation in the anteriorchamber. Scoring was as follows.

-   0=None.-   1=1+.-   2=2+.-   3=3+.-   4=4+.

The lens was observed for any cataracts. Scoring was as follows.

-   0=Lens clear.-   1=Anterior (cortical/capsular).-   2=Nuclear.-   3=Posterior.-   4=Equatorial.

The vitreous was observed for any abnormalities. Scoring was as follows.

-   0=Clear vitreous.-   1=Few scattered opacities, fundus unimpaired.-   2=Moderate scattered opacities.-   3=Many opacities, marked blurring of fundus details.-   4=Dense opacities, no fundus view.

The vitreous was observed for any hemorrhage. Scoring was as follows.

-   0=Normal.-   1=1-25%.-   2=26-50%.-   3=51-75%.-   4=76-100%.

During a retinal detachment, bleeding from small retinal blood vesselsmay cloud the interior of the eye, which is normally filled withvitreous fluid. Retinal detachment scoring was as follows.

-   0=None.-   1=Rhegmatogenous (retinal detachment occurs when subretinal fluid    accumulates in the potential space between the neurosensory retina    and the underlying retinal pigment epithelium).-   2=Exudative (occurs due to inflammation, injury, or vascular    abnormalities that result in fluid accumulating underneath the    retina without the presence of a hole, tear, or break).-   3=Tractional (occurs when fibrous or fibrovascular tissue, caused by    an injury, inflammation, or neovascularization that pulls the    sensory retina from the retinal pigment epithelium).

Retinal hemorrhage was observed through abnormal bleeding of the bloodvessels in the retina. Scoring was as follows.

-   0=Normal.-   1=1-25%.-   2=26-50%.-   3=51-75%.-   4=76-100%.

Choroidal/retinal inflammation was observed through inflammation of theretina and/or choroid. Scoring was as follows.

-   0=None.-   1=Mild.-   2=Moderate.-   3=Severe.

IOP measurements were performed twice (AM and PM) at baseline (prior tothe start of dosing), twice (AM and PM) on Days 1 and 7, and once daily(AM) on Days 2-6 and Day 8. Prior to taking all IOP measurements, 1 to 2drops of a 0.5% proparacaine solution were applied to the eye as atopical anesthetic. IOP measurements were performed with apneumotonometer. AM IOP measurements were performed 2 hours after AMdosing; the only exceptions were Day 8 AM measurements, which wereperformed 24 hours after the final dose. PM IOP measurements wereperformed ˜5 hours (baseline and Day 1) or ˜4 hours (Day 7) after AM IOPmeasurements, prior to PM dosing, with at least 15 minutes elapsingbetween anesthetic application for PM IOP measurements and PM dosing.The final round of slit-lamp examinations was performed on Day 8.

All animals exhibited normal health and activity throughout the study.All animals had no ocular anomalies during the baseline pre-screeningexamination. On Day 1, mild conjunctival congestion (scores=1) wasobserved across groups as follows: one animal in Group 1 (third eyelidof the left eye only); all five animals in Group 2 (both eyes (OU) inone animal, left (OS) or right eye (OD) only in the remaining fouranimals); one animal also exhibited mild conjunctival swelling (OS); twoanimals in Group 3 (both OS); one animal in Group 4 (OS); three animalsin Group 5 (one OS, one OU with only the third eyelid affected in oneeye).

On Day 4, mild conjunctival congestion (scores=1) was found in thefollowing groups: two animals in Group 2 (one OU, one OD); two animalsin Group 3 (one OU, one OD); one animal in Group 4 (OU, third eyelidonly); none in Groups 1 and 5.

No ocular anomalies were observed on Day 8.

Over the course of dosing, lower IOP values compared to Group 1(Vehicle) were found in Groups 3 (1.2 mg/eye topical Compound 1 (sodiumsalt), BID) and 4 (1.2 mg/eye topical Compound 1 (sodium salt), QD), butnot Group 2 (0.45 mg/eye topical Compound 1 (sodium salt), BID). FIG. 17shows the raw IOP values for vehicle control (Group 1) and the four testGroups 2-5. FIG. 18 shows the differences in IOP from vehicle control,over the course of the 8 days. Group 1 is represented by circles, Group2 by squares, Group 3 by triangles pointing up, Group 4 by trianglespointing down, and Group 5 by diamonds. Lower IOP values compared toGroup 1 were also seen in the early part of the study in Group 5 (10mg/kg subcutaneous Compound 1 (sodium salt), BID), but the differencedecreased towards the end of the study (FIG. 17 and FIG. 18). Theapparent reduction in intraocular pressure values in Groups 3 and 4persisted on Day 7, the last day of dosing as shown in FIG. 19 (raw IOPmeasurements) and FIG. 20 (decrease in IOP from vehicle control), andDay 8, 24 hours after the end of dosing as shown in FIG. 21 (raw IOPmeasurements) and FIG. 22 (decrease in IOP from vehicle control)).Intraocular pressure measurements are shown in TABLES 22-25, below.

Topically administered Compound 1 (sodium salt) was observed to reduceintraocular pressure at the 1.2 mg/eye dose, whether dosed QD or BID.Reduction in IOP values was slightly more consistent compared to vehiclecontrol with 10 mg/kg subcutaneous Compound 1 (sodium salt). No adverseeffects of the test article on general health were observed during thestudy. Mild conjunctival congestion observed in some animals appeared tobe unrelated to the test article, as the incidence rate was highest inthe group receiving the lowest topical dose, and the incidence ratedecreased rather than increased with repeated dosing.

TABLE 22 Acclimation Acclimation Acclimation Acclimation AcclimationAcclimation Animal (Day −10, AM) (Day −10, PM) (Day −9, AM) (Day −9, PM)(Day −8, AM) (Day −8, PM) Group ID OD OS OD OS OD OS OD OS OD OS OD OS 1A 19.0 21.8 23.5 23.3 22.0 22.5 24.5 23.0 23.8 24.2 24.8 26.2 B 23.324.2 25.5 24.7 24.8 25.2 25.2 25.7 24.3 23.5 26.7 25.8 C 20.0 19.8 22.221.5 22.8 22.5 22.8 23.2 22.0 23.3 24.5 25.0 D 23.7 24.3 24.8 24.5 24.324.3 25.3 25.2 23.2 24.3 26.2 27.3 E 22.3 23.2 24.3 24.5 23.3 23.8 24.223.8 22.7 23.7 23.5 24.7 Average 21.7 22.7 24.1 23.7 23.4 23.7 24.4 24.223.2 23.8 25.1 25.8 Std Dev 2.1 1.9 1.3 1.3 1.1 1.2 1.0 1.2 0.9 0.4 1.31.0 2 F 24.0 24.3 25.2 25.0 24.3 24.8 25.0 24.7 20.8 22.0 26.2 25.3 G21.0 22.3 24.5 24.8 24.5 24.5 25.7 25.8 24.7 24.5 26.0 26.5 H 23.3 23.724.5 24.7 23.2 24.5 26.2 26.0 24.7 25.2 28.2 28.7 I 21.5 22.3 23.2 23.022.5 23.3 23.8 24.3 18.7 22.0 23.7 23.5 J 22.2 24.0 25.2 25.7 24.3 24.727.3 28.0 24.7 25.8 27.7 27.0 Average 22.4 23.3 24.5 24.6 23.8 24.4 25.625.8 22.7 23.9 26.4 26.2 Std Dev 1.2 1.0 0.8 1.0 0.9 0.6 1.3 1.4 2.8 1.81.8 1.9 3 K 21.5 22.7 24.5 24.2 20.3 20.7 23.7 24.7 18.3 20.0 24.7 25.8L 19.3 20.8 22.8 23.0 21.8 22.3 22.8 22.3 20.2 20.3 23.2 24.0 M 20.321.2 23.8 24.2 23.3 24.0 25.0 24.7 23.8 23.2 24.7 25.8 N 20.8 21.3 24.225.0 22.3 23.3 24.8 24.7 23.2 24.5 24.3 24.5 O 22.2 23.3 23.5 23.8 23.824.0 25.2 25.0 23.5 24.0 24.3 25.2 Average 20.8 21.9 23.8 24.0 22.3 22.924.3 24.3 21.8 22.4 24.2 25.1 Std Dev 1.1 1.1 0.7 0.7 1.4 1.4 1.0 1.12.4 2.1 0.6 0.8 4 P 22.5 23.0 25.3 23.8 23.7 21.0 24.8 24.8 22.0 22.023.5 24.0 Q 21.8 21.5 24.5 23.2 24.2 23.3 25.8 24.5 24.0 23.8 27.5 27.2R 20.8 20.7 25.0 24.3 21.5 21.0 26.2 25.0 22.0 20.7 25.0 25.5 S 20.821.2 24.0 23.3 21.7 22.8 24.3 23.5 22.0 22.5 25.3 24.3 T 19.0 20.3 24.525.2 20.3 23.2 24.2 25.0 21.3 24.0 24.5 25.3 Average 21.0 21.3 24.7 24.022.3 22.3 25.1 24.6 22.3 22.6 25.2 25.3 Std Dev 1.3 1.0 0.5 0.8 1.6 1.20.9 0.6 1.0 1.4 1.5 1.3 5 U 22.7 22.0 24.8 24.8 23.7 24.0 25.2 25.2 23.523.7 26.0 25.0 V 23.3 23.8 25.5 24.0 22.3 23.2 25.0 24.7 22.5 21.2 25.324.3 W 23.2 23.2 24.7 24.5 24.0 23.7 25.3 25.2 22.7 23.7 25.2 25.8 X23.3 23.5 25.7 24.5 24.0 24.5 24.8 25.5 23.7 24.7 25.3 25.7 Y 21.5 21.823.7 23.7 20.7 20.7 23.0 23.8 20.7 21.2 24.7 25.8 Average 22.8 22.9 24.924.3 22.9 23.2 24.7 24.9 22.6 22.9 25.3 25.3 Std Dev 0.8 0.9 0.8 0.4 1.41.5 0.9 0.7 1.2 1.6 0.5 0.7 OD: Right eye; OS: left eye

TABLE 23 Acclimation Acclimation Acclimation Baseline Baseline Animal(Day −7, AM) (Day −7, PM) (Day −2, AM) (Day −1, AM) (Day −1, PM) GroupID OD OS OD OS OD OS OD OS OD OS 1 A 24.2 25.2 22.3 24.0 24.0 24.7 21.322.7 22.8 24.7 B 24.8 24.0 26.3 26.0 24.7 24.7 24.2 24.5 25.7 24.8 C18.8 18.7 24.8 24.7 23.3 23.7 24.5 24.2 24.2 23.5 D 22.7 23.0 25.0 25.224.3 25.0 23.8 24.2 24.5 26.3 E 23.3 23.7 24.7 24.5 23.0 23.7 24.7 24.024.7 25.5 Average 22.8 22.9 24.6 24.9 23.9 24.3 23.7 23.9 24.4 25.0 StdDev 2.3 2.5 1.4 0.8 0.7 0.6 1.4 0.7 1.0 1.1 2 F 23.2 23.5 25.5 24.8 24.224.5 26.2 23.2 25.7 26.2 G 24.8 25.2 26.3 24.7 25.0 25.0 24.3 24.8 24.825.3 H 25.8 26.0 26.5 26.8 25.0 25.5 26.5 26.8 27.7 28.2 I 20.7 22.225.0 24.3 23.5 24.5 22.5 23.7 23.3 23.7 J 23.7 24.8 26.5 27.8 25.0 25.524.2 25.3 27.7 28.0 Average 23.6 24.3 26.0 25.7 24.5 25.0 24.7 24.8 25.826.3 Std Dev 2.0 1.5 0.7 1.5 0.7 0.5 1.6 1.4 1.9 1.9 3 K 22.3 23.0 23.824.2 23.5 23.8 24.3 24.2 24.0 23.3 L 19.8 19.8 23.7 24.3 21.5 21.0 21.723.0 24.8 24.7 M 21.8 21.8 24.2 24.0 23.5 24.3 22.7 23.0 24.3 25.2 N24.2 24.5 23.7 24.0 22.3 23.5 22.5 22.8 24.3 25.5 O 24.5 23.8 26.2 25.323.2 23.0 24.7 24.7 26.2 27.3 Average 22.5 22.6 24.3 24.4 22.8 23.1 23.223.5 24.7 25.2 Std Dev 1.9 1.8 1.1 0.6 0.9 1.3 1.3 0.8 0.9 1.5 4 P 23.322.0 25.0 22.7 23.5 23.5 24.0 23.8 23.3 22.8 Q 22.8 22.5 25.8 24.3 24.824.5 24.5 24.8 24.5 25.2 R 19.0 18.7 25.3 24.2 23.5 23.8 23.3 22.5 24.024.2 S 23.7 22.7 25.0 25.7 22.7 24.0 21.5 23.8 25.2 25.5 T 19.7 22.024.8 25.2 23.3 24.3 23.2 24.8 23.5 24.3 Average 21.7 21.6 25.2 24.4 23.624.0 23.3 23.9 24.1 24.4 Std Dev 2.2 1.6 0.4 1.1 0.8 0.4 1.1 0.9 0.8 1.05 U 21.3 23.0 26.7 24.3 22.8 22.7 25.5 24.2 24.2 25.5 V 23.0 23.2 26.726.7 24.2 25.2 23.8 24.0 25.2 26.3 W 21.5 23.0 24.2 25.0 21.3 21.8 23.523.8 25.5 24.7 X 24.2 25.0 25.0 26.5 24.8 25.0 26.2 25.8 25.8 26.2 Y20.7 20.2 23.0 23.3 24.8 24.8 23.8 23.3 26.5 26.3 Average 22.1 22.9 25.125.2 23.6 23.9 24.6 24.2 25.4 25.8 Std Dev 1.4 1.7 1.6 1.4 1.5 1.5 1.20.9 0.9 0.7 OD: Right eye; OS: left eye

TABLE 24 Animal Day 1, AM Day 1, PM Day 2, AM Day 3, AM Day 4, AM Day 5,AM Group ID OD OS OD OS OD OS OD OS OD OS OD OS 1 A 20.7 21.5 20.7 22.721.2 22.3 20.8 24.0 22.0 23.7 26.0 28.2 B 24.7 23.3 24.2 24.5 23.8 23.525.8 26.2 27.3 26.3 25.0 24.8 C 23.2 21.8 25.3 24.3 22.0 22.5 24.8 24.524.3 25.0 24.5 23.8 D 23.0 23.0 22.2 23.3 21.2 23.3 22.3 23.0 24.5 25.223.3 24.2 E 23.5 23.0 24.2 24.2 21.3 22.3 23.7 23.7 24.8 24.8 23.0 22.5Average 23.0 22.5 23.3 23.8 21.9 22.8 23.5 24.3 24.6 25.0 24.4 24.7 StdDev 1.5 0.8 1.9 0.8 1.1 0.6 2.0 1.2 1.9 1.0 1.2 2.1 2 F 20.3 20.7 24.824.8 22.0 21.8 25.0 25.3 23.8 23.0 28.8 28.8 G 23.7 23.3 24.8 24.2 22.722.3 24.2 23.5 22.0 22.7 22.8 25.0 H 24.0 25.2 29.5 28.8 25.0 24.3 26.026.0 26.7 26.3 28.0 28.0 I 20.7 23.3 22.0 25.3 18.3 20.8 20.8 23.0 21.323.5 20.7 24.2 J 21.7 23.8 26.2 27.2 21.7 21.5 23.8 24.5 25.7 26.2 25.726.3 Average 22.1 23.3 25.5 26.1 21.9 22.2 24.0 24.5 23.9 24.3 25.2 26.5Std Dev 1.7 1.6 2.7 1.9 2.4 1.3 1.9 1.2 2.3 1.8 3.4 2.0 3 K 23.2 23.823.8 24.5 17.5 19.3 19.2 20.0 23.2 23.3 21.5 22.3 L 20.7 23.0 22.7 23.718.5 20.2 20.0 20.8 19.8 21.7 18.8 19.8 M 24.0 24.7 24.7 26.8 24.3 24.023.0 22.7 23.8 24.2 22.3 23.5 N 20.2 21.5 25.2 25.0 18.2 18.2 19.2 19.324.8 24.5 21.2 20.7 O 22.2 23.0 24.3 24.5 25.5 24.5 22.2 23.0 22.2 22.323.7 23.7 Average 22.0 23.2 24.1 24.9 20.8 21.2 20.7 21.2 22.8 23.2 21.522.0 Std Dev 1.6 1.2 1.0 1.2 3.8 2.8 1.8 1.6 1.9 1.2 1.8 1.7 4 P 23.222.0 21.3 20.8 20.5 21.0 21.8 20.0 21.5 21.8 23.8 22.7 Q 22.0 23.3 24.023.3 19.8 19.7 23.5 23.5 22.8 23.2 20.8 21.7 R 20.7 19.2 23.3 22.5 20.019.3 21.0 19.5 20.8 20.0 20.5 18.7 S 20.2 21.3 22.8 23.8 19.3 19.7 18.521.2 22.2 24.3 19.7 22.0 T 19.8 21.2 24.2 25.5 20.3 21.0 19.0 20.3 20.723.5 20.3 21.2 Average 21.2 21.4 23.1 23.2 20.0 20.1 20.8 20.9 21.6 22.621.0 21.2 Std Dev 1.4 1.5 1.1 1.7 0.5 0.8 2.1 1.6 0.9 1.7 1.6 1.5 5 U21.5 24.3 24.3 20.5 17.7 18.7 16.8 17.5 20.0 18.7 21.5 20.7 V 22.2 22.822.7 22.8 20.2 21.2 20.2 21.5 21.2 22.2 14.0 21.0 W 21.5 21.8 26.2 27.221.5 21.7 20.3 21.5 24.7 24.7 23.7 23.2 X 23.8 24.2 24.0 26.3 25.3 24.022.8 22.2 22.5 23.3 26.7 25.8 Y 22.7 24.7 19.3 21.0 22.7 22.8 23.3 23.721.2 22.2 26.3 26.2 Average 22.3 23.6 23.3 23.6 21.5 21.7 20.7 21.3 21.922.2 22.4 23.4 Std Dev 1.0 1.2 2.5 3.0 2.9 2.0 2.6 2.3 1.8 2.2 5.2 2.6OD: Right eye; OS: left eye

TABLE 25 Animal Day 6, AM Day 7, AM Day 7, PM Day 8, AM Group ID OD OSOD OS OD OS OD OS 1 A 26.8 26.8 23.3 24.8 22.5 24.3 25.7 26.2 B 26.226.0 24.8 25.7 24.8 25.3 25.5 25.5 C 23.8 25.2 24.3 24.0 24.3 23.2 24.024.2 D 24.0 17.7 24.7 25.7 24.7 25.5 24.0 24.5 E 24.5 25.0 25.0 25.224.7 24.5 25.7 25.3 Average 25.1 24.1 24.4 25.1 24.2 24.6 25.0 25.1 StdDev 1.4 3.7 0.7 0.7 1.0 0.9 0.9 0.8 2 F 26.8 26.5 24.2 24.2 24.8 24.225.8 25.8 G 25.5 24.7 23.5 23.3 25.2 25.3 25.7 25.7 H 27.0 26.2 26.326.5 27.2 28.0 26.2 26.5 I 23.7 25.0 19.8 22.7 22.2 24.7 23.2 24.7 J24.5 24.7 24.8 26.0 26.0 26.0 23.5 23.0 Average 25.5 25.4 23.7 24.5 25.125.6 24.9 25.1 Std Dev 1.4 0.9 2.4 1.7 1.9 1.5 1.4 1.4 3 K 24.3 25.316.5 18.8 23.5 24.7 22.3 23.7 L 23.3 24.5 18.3 19.2 24.3 23.8 22.7 23.0M 26.8 27.3 25.3 25.8 24.7 26.7 25.2 25.2 N 22.3 22.2 23.5 24.2 22.022.2 24.5 24.3 O 24.2 24.2 22.7 22.0 23.8 23.8 22.5 23.5 Average 24.224.7 21.3 22.0 23.7 24.2 23.4 23.9 Std Dev 1.7 1.9 3.7 3.1 1.0 1.6 1.30.8 4 P 23.2 22.2 23.3 22.2 24.5 24.3 22.8 22.7 Q 24.7 24.5 23.8 23.726.0 26.0 24.7 24.2 R 22.2 21.7 20.2 20.0 24.7 23.7 21.2 20.7 S 22.223.5 23.0 23.8 22.7 23.5 22.3 23.5 T 20.3 24.2 22.5 25.2 25.0 26.0 22.323.2 Average 22.5 23.2 22.6 23.0 24.6 24.7 22.7 22.8 Std Dev 1.6 1.2 1.42.0 1.2 1.2 1.3 1.3 5 U 24.8 24.7 22.7 24.0 22.7 23.5 22.8 22.0 V 23.824.0 23.3 24.0 24.5 24.5 25.2 24.8 W 25.5 25.7 23.5 23.7 25.5 24.3 24.024.2 X 25.2 25.8 24.7 22.7 25.5 25.3 26.0 25.5 Y 23.2 24.7 25.2 25.222.3 23.7 24.3 23.7 Average 24.5 25.0 23.9 23.9 24.1 24.3 24.5 24.0 StdDev 1.0 0.8 1.0 0.9 1.5 0.7 1.2 1.3 OD: Right eye; OS: left eye

Embodiments

The following non-limiting embodiments provide illustrative examples ofthe invention, but do not limit the scope of the invention.

Embodiment 1. A method for reducing intraocular pressure in a subject inneed thereof, the method comprising administering to the subject atherapeutically-effective amount of a Tie-2 activator, wherein theadministration reduces the intraocular pressure by about 0.1 mmHg toabout 9 mmHg compared to absence of administration.

Embodiment 2. The method of embodiment 1, wherein the Tie-2 activatorbinds a phosphatase.

Embodiment 3. The method of any one of embodiments 1-2, wherein theTie-2 activator inhibits a phosphatase.

Embodiment 4. The method of any one of embodiments 1-3, wherein theTie-2 activator binds HPTP-β.

Embodiment 5. The method of any one of embodiments 1-4, wherein theTie-2 activator inhibits HPTP-β.

Embodiment 6. The method of any one of embodiments 1-5, wherein theTie-2 activator is a phosphate mimetic.

Embodiment 7. The method of any one of embodiments 1-6, wherein theTie-2 activator is a compound of the formula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; and Y is H, aryl,heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any ofwhich is substituted or unsubstituted, or

wherein:

-   -   L² is alkylene, alkenylene, or alkynylene, any of which is        substituted or unsubstituted, or together with the nitrogen atom        to which L² is bound forms an amide linkage, a carbamate        linkage, or a sulfonamide linkage, or a chemical bond, or        together with any of R^(a), R^(b), R^(c), and R^(d) forms a ring        that is substituted or unsubstituted;    -   R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted, or together with        any of L², R^(b), R^(c), and R^(d) forms a ring that is        substituted or unsubstituted;    -   R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted, or together with        any of L², R^(a), R^(c), and R^(d) forms a ring that is        substituted or unsubstituted;    -   R^(c) is H or alkyl which is substituted or unsubstituted, or        together with any of L², R^(a), R^(b), and R^(d) forms a ring        that is substituted or unsubstituted;    -   R^(d) is H or alkyl which is substituted or unsubstituted, or        together with any of L², R^(a), R^(b), and R^(c) forms a ring        that is substituted or unsubstituted; and    -   R^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted,    -   or a pharmaceutically-acceptable salt, tautomer, or zwitterion        thereof.

Embodiment 8. The method of embodiment 7, wherein:

-   -   Aryl¹ is substituted or unsubstituted phenyl;    -   Aryl² is substituted or unsubstituted heteroaryl; and    -   X is alkylene.

Embodiment 9. The method of any one of embodiments 7-8, wherein:

-   -   Aryl¹ is substituted phenyl;    -   Aryl² is substituted heteroaryl; and    -   X is methylene.

Embodiment 10. The method of embodiment 1, wherein the compound thatactivates Tie-2 is a compound of the formula:

wherein

-   -   Aryl¹ is para-substituted phenyl;    -   Aryl² is substituted heteroaryl;    -   X is methylene;    -   L² is alkylene, alkenylene, or alkynylene, any of which is        substituted or unsubstituted, or together with the nitrogen atom        to which L² is bound forms an amide linkage, a carbamate        linkage, or a sulfonamide linkage, or a chemical bond;    -   R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted;    -   R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted;    -   R^(c) is H or alkyl which is substituted or unsubstituted; and    -   R^(d) is H or alkyl which is substituted or unsubstituted.

Embodiment 11. The method of embodiment 10, wherein:

-   -   Aryl¹ is para-substituted phenyl;    -   Aryl² is a substituted thiazole moiety;    -   X is methylene;    -   L² together with the nitrogen atom to which L² is bound forms a        carbamate linkage;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(c) is H; and    -   R^(d) is H.

Embodiment 12. The method of any one of embodiments 7-11, wherein Aryl²is:

wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted; and    -   R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted.

Embodiment 13. The method of embodiment 12, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted;        and    -   R^(f) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted.

Embodiment 14. The method of any one of embodiments 12-13, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of        which is substituted or unsubstituted; and    -   R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which        is substituted or unsubstituted.

Embodiment 15. The method of any one of embodiments 12-14, wherein:

-   -   Aryl¹ is 4-phenylsulfamic acid;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(e) is H; and    -   R^(f) is heteroaryl.

Embodiment 16. The method of any one of embodiments 1-15, wherein thecompound or Tie-2 activator is:

Embodiment 17. The method of any one of embodiments 1-15, wherein thecompound or Tie-2 activator is:

Embodiment 18. The method of any one of embodiments 12-14, wherein:

-   -   Aryl¹ is 4-phenylsulfamic acid;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(e) is H; and    -   R^(f) is alkyl.

Embodiment 19. The method of any one of embodiments 1-14 and 18, whereinthe compound or Tie-2 activator is:

Embodiment 20. The method of any one of embodiments 1-14 and 18, whereinthe compound or Tie-2 activator is:

Embodiment 21. The method of any one of embodiments 7-11, wherein Aryl²is:

wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted; and    -   R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted.

Embodiment 22. The method of embodiment 21, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted;        and    -   R^(f) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted.

Embodiment 23. The method of any one of embodiments 21-22, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of        which is substituted or unsubstituted; and    -   R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which        is substituted or unsubstituted.

Embodiment 24. The method of embodiment 21, wherein:

-   -   Aryl¹ is 4-phenylsulfamic acid;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(e) is H; and    -   R^(f) is heteroaryl.

Embodiment 25. The method of any one of embodiments 1-11 and 21-24,wherein the compound or Tie-2 activator is:

Embodiment 26. The method of any one of embodiments 1-11 and 21-24,wherein the compound or Tie-2 activator is:

Embodiment 27. The method of any one of embodiments 1-26, wherein thetherapeutically-effective amount is from about 1 mg to about 100 mg.

Embodiment 28. The method of any one of embodiments 1-27, wherein thetherapeutically-effective amount is from about 0.5 mg to about 30 mg.

Embodiment 29. The method of any one of embodiments 1-28, wherein thetherapeutically-effective amount is about 15 mg.

Embodiment 30. The method of any one of embodiments 1-28, wherein thetherapeutically-effective amount is about 22.5 mg.

Embodiment 31. The method of any one of embodiments 1-28, wherein thetherapeutically-effective amount is about 30 mg.

Embodiment 32. The method of any one of embodiments 1-31, wherein theadministration is to an eye of the subject.

Embodiment 33. The method of any one of embodiments 1-32, wherein theadministration is intravitreal.

Embodiment 34. The method of any one of embodiments 1-31, wherein theadministration is subcutaneous.

Embodiment 35. The method of any one of embodiments 1-32, wherein theadministration is topical.

Embodiment 36. The method of any one of embodiments 1-32 and 35 whereinthe administration is topical to an eye of the subject.

Embodiment 37. The method of any one of embodiments 1-32, 35, and 36wherein the Tie-2 activator, or a pharmaceutically-acceptable saltthereof, is formulated as a drop.

Embodiment 38. The method of any one of embodiments 1-32 and 35-37wherein the Tie-2 activator, or a pharmaceutically-acceptable saltthereof, is formulated as a drop, wherein the drop is administered to aneye of the subject.

Embodiment 39. The method of any one of embodiments 1-38, wherein thesubject is a human.

Embodiment 40. The method of any one of embodiments 1-39, wherein theintraocular pressure is reduced by at least about 2 mmHg.

Embodiment 41. The method of any one of embodiments 1-40, wherein thesubject has glaucoma, wherein the intraocular pressure is associatedwith glaucoma.

Embodiment 42. The method of any one of embodiments 1-41, wherein theintraocular pressure is ocular hypertension.

Embodiment 43. The method of embodiment 42, wherein the subject hasglaucoma, wherein the ocular hypertension is associated with glaucoma.

Embodiment 44. A method for treating glaucoma in a subject in needthereof, the method comprising administering to the subject atherapeutically-effective amount of a Tie-2 activator, wherein theadministration reduces intraocular pressure by about 0.1 mmHg to about 9mmHg compared to absence of administration.

Embodiment 45. The method of embodiment 44, wherein the Tie-2 activatorbinds a phosphatase.

Embodiment 46. The method of any one of embodiments 44-45, wherein theTie-2 activator inhibits a phosphatase.

Embodiment 47. The method of any one of embodiments 44-46, wherein theTie-2 activator binds HPTP-β.

Embodiment 48. The method of any one of embodiments 44-47, wherein theTie-2 activator inhibits HPTP-β.

Embodiment 49. The method of any one of embodiments 44-48, wherein theTie-2 activator is a phosphate mimetic.

Embodiment 50. The method of any one of embodiments 44-49, wherein theTie-2 activator is a compound of the formula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; and Y is H, aryl,heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any ofwhich is substituted or unsubstituted, or

wherein:

-   -   L² is alkylene, alkenylene, or alkynylene, any of which is        substituted or unsubstituted, or together with the nitrogen atom        to which L² is bound forms an amide linkage, a carbamate        linkage, or a sulfonamide linkage, or a chemical bond, or        together with any of R^(a), R^(b), R^(c), and R^(d) forms a ring        that is substituted or unsubstituted;    -   R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted, or together with        any of L², R^(b), R^(c), and R^(d) forms a ring that is        substituted or unsubstituted;    -   R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted, or together with        any of L², R^(a), R^(c), and R^(d) forms a ring that is        substituted or unsubstituted;    -   R^(c) is H or alkyl which is substituted or unsubstituted, or        together with any of L², R^(a), R^(b), and R^(d) forms a ring        that is substituted or unsubstituted;    -   R^(d) is H or alkyl which is substituted or unsubstituted, or        together with any of L², R^(a), R^(b), and R^(c) forms a ring        that is substituted or unsubstituted; and    -   R^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted,    -   or a pharmaceutically-acceptable salt, tautomer, or zwitterion        thereof.

Embodiment 51. The method of embodiment 50, wherein:

-   -   Aryl¹ is substituted or unsubstituted phenyl;    -   Aryl² is substituted or unsubstituted heteroaryl; and    -   X is alkylene.

Embodiment 52. The method of any one of embodiments 50-51, wherein:

-   -   Aryl¹ is substituted phenyl;    -   Aryl² is substituted heteroaryl; and    -   X is methylene.

Embodiment 53. The method of embodiment 44, wherein the compound thatactivates Tie-2 is a compound of the formula:

wherein

-   -   Aryl¹ is para-substituted phenyl;    -   Aryl² is substituted heteroaryl;    -   X is methylene;    -   L² is alkylene, alkenylene, or alkynylene, any of which is        substituted or unsubstituted, or together with the nitrogen atom        to which L² is bound forms an amide linkage, a carbamate        linkage, or a sulfonamide linkage, or a chemical bond;    -   R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted;    -   R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted;    -   R^(c) is H or alkyl which is substituted or unsubstituted; and    -   R^(d) is H or alkyl which is substituted or unsubstituted.

Embodiment 54. The method of embodiment 51, wherein:

-   -   Aryl¹ is para-substituted phenyl;    -   Aryl² is a substituted thiazole moiety;    -   X is methylene;    -   L² together with the nitrogen atom to which L² is bound forms a        carbamate linkage;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(c) is H; and    -   R^(d) is H.

Embodiment 55. The method of any one of embodiments 50-54, wherein Aryl2is:

wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted; and    -   R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted.

Embodiment 56. The method of embodiment 55, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted;        and    -   R^(f) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted.

Embodiment 57. The method of any one of embodiments 55-56, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of        which is substituted or unsubstituted; and    -   R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which        is substituted or unsubstituted.

Embodiment 58. The method of any one of embodiments 55-57, wherein:

-   -   Aryl¹ is 4-phenylsulfamic acid;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(e) is H; and    -   R^(f) is heteroaryl.

Embodiment 59. The method of any one of embodiments 44-58, wherein thecompound or Tie-2 activator is:

Embodiment 60. The method of any one of embodiments 44-58, wherein thecompound or Tie-2 activator is:

Embodiment 61. The method of any one of embodiments 55-57, wherein:

-   -   Aryl¹ is 4-phenylsulfamic acid;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(e) is H; and    -   R^(f) is alkyl.

Embodiment 62. The method of any one of embodiments 44-57 and 61,wherein the compound or Tie-2 activator is:

Embodiment 63. The method of any one of embodiments 44-57 and 61,wherein the compound or Tie-2 activator is:

Embodiment 64. The method of any one of embodiments 50-54, wherein Aryl²is:

wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted; and    -   R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an        alkoxy group, an ether group, a carboxylic acid group, a        carboxaldehyde group, an ester group, an amine group, an amide        group, a carbonate group, a carbamate group, a thioether group,        a thioester group, a thioacid group, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,        any of which is substituted or unsubstituted.

Embodiment 65. The method of embodiment 64, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted;        and    -   R^(f) is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl,        arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl, any of which is substituted or unsubstituted.

Embodiment 66. The method of any one of embodiments 64-65, wherein:

-   -   R^(e) is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of        which is substituted or unsubstituted; and    -   R^(f) is alkyl, aryl, heterocyclyl, or heteroaryl, any of which        is substituted or unsubstituted.

Embodiment 67. The method of embodiment 64, wherein:

-   -   Aryl¹ is 4-phenylsulfamic acid;    -   R^(a) is alkyl, which is substituted or unsubstituted;    -   R^(b) is arylalkyl, which is substituted or unsubstituted;    -   R^(e) is H; and    -   R^(f) is heteroaryl.

Embodiment 68. The method of any one of embodiments 44-50 and 64-67,wherein the compound or Tie-2 activator is:

Embodiment 69. The method of any one of embodiments 44-50 and 64-67,wherein the compound or Tie-2 activator is:

Embodiment 70. The method of any one of embodiments 44-69, wherein thetherapeutically-effective amount is from about 1 mg to about 100 mg.

Embodiment 71. The method of any one of embodiments 44-70, wherein thetherapeutically-effective amount is from about 0.5 mg to about 30 mg.

Embodiment 72. The method of any one of embodiments 44-71, wherein thetherapeutically-effective amount is about 15 mg.

Embodiment 73. The method of any one of embodiments 44-71, wherein thetherapeutically-effective amount is about 22.5 mg.

Embodiment 74. The method of any one of embodiments 44-71, wherein thetherapeutically-effective amount is about 30 mg.

Embodiment 75. The method of any one of embodiments 44-74, wherein theadministration is to an eye of the subject.

Embodiment 76. The method of any one of embodiments 44-75, wherein theadministration is intravitreal.

Embodiment 77. The method of embodiment 44-74, wherein theadministration is subcutaneous.

Embodiment 78. The method of any one of any one of embodiments 44-75,wherein the administration is topical.

Embodiment 79. The method of any one of embodiments 44-75, wherein theadministration is topical to an eye of the subject.

Embodiment 80. The method of any one of embodiments 44-75, 78, or 79,wherein the Tie-2 activator, or a pharmaceutically-acceptable saltthereof, is formulated as a drop.

Embodiment 81. The method of any one of embodiments 44-75, and 78-80wherein the Tie-2 activator, or a pharmaceutically-acceptable saltthereof, is formulated as a drop, wherein the drop is administered to aneye of the subject.

Embodiment 82. The method of any one of embodiments 44-81, wherein thesubject is a human.

Embodiment 83. The method of any one of embodiments 44-82, wherein theintraocular pressure is reduced by at least about 2 mmHg.

Embodiment 84. The method of any one of embodiments 44-83, wherein theintraocular pressure is ocular hypertension.

What is claimed is:
 1. A method for reducing intraocular pressure in asubject in need thereof, the method comprising administering to thesubject a therapeutically-effective amount of a Tie-2 activator, whereinthe administration reduces the intraocular pressure by about 0.1 mmHg toabout 9 mmHg compared to absence of administration.
 2. The method ofclaim 1, wherein the Tie-2 activator binds a phosphatase.
 3. The methodof claim 1, wherein the Tie-2 activator inhibits a phosphatase.
 4. Themethod of claim 1, wherein the Tie-2 activator binds HPTP-β.
 5. Themethod of claim 1, wherein the Tie-2 activator inhibits HPTP-β.
 6. Themethod of claim 1, wherein the Tie-2 activator is a phosphate mimetic.7. The method of claim 1, wherein the Tie-2 activator is a compound ofthe formula:

wherein: Aryl¹ is an aryl group which is substituted or unsubstituted;Aryl² is an aryl group which is substituted or unsubstituted; X isalkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, anamide linkage, an ester linkage, a thioether linkage, a carbamatelinkage, a carbonate linkage, a sulfone linkage, any of which issubstituted or unsubstituted, or a chemical bond; and Y is H, aryl,heteroaryl, NH(aryl), NH(heteroaryl), NHSO₂R^(g), or NHCOR^(g), any ofwhich is substituted or unsubstituted, or

wherein: L² is alkylene, alkenylene, or alkynylene, any of which issubstituted or unsubstituted, or together with the nitrogen atom towhich L² is bound forms an amide linkage, a carbamate linkage, or asulfonamide linkage, or a chemical bond, or together with any of R^(a),R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(a) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(b), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted, or together with any of L²,R^(a), R^(c), and R^(d) forms a ring that is substituted orunsubstituted; R^(c) is H or alkyl which is substituted orunsubstituted, or together with any of L², R^(a), R^(b), and R^(d) formsa ring that is substituted or unsubstituted; R^(d) is H or alkyl whichis substituted or unsubstituted, or together with any of L², R^(a),R^(b), and R^(c) forms a ring that is substituted or unsubstituted; andR^(g) is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted, or a pharmaceutically-acceptable salt,tautomer, or zwitterion thereof.
 8. The method of claim 7, wherein:Aryl¹ is substituted or unsubstituted phenyl; Aryl² is substituted orunsubstituted heteroaryl; and X is alkylene.
 9. The method of claim 8,wherein: Aryl¹ is substituted phenyl; Aryl² is substituted heteroaryl;and X is methylene.
 10. The method of claim 9, wherein the compound thatactivates Tie-2 is a compound of the formula:

wherein Aryl¹ is para-substituted phenyl; Aryl² is substitutedheteroaryl; X is methylene; L² is alkylene, alkenylene, or alkynylene,any of which is substituted or unsubstituted, or together with thenitrogen atom to which L² is bound forms an amide linkage, a carbamatelinkage, or a sulfonamide linkage, or a chemical bond; R^(a) is H,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted; R^(b) is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, any of which is substituted or unsubstituted; R^(c) isH or alkyl which is substituted or unsubstituted; and R^(d) is H oralkyl which is substituted or unsubstituted.
 11. The method of claim 10,wherein: Aryl¹ is para-substituted phenyl; Aryl² is a substitutedthiazole moiety; X is methylene; L² together with the nitrogen atom towhich L² is bound forms a carbamate linkage; R^(a) is alkyl, which issubstituted or unsubstituted; R^(b) is arylalkyl, which is substitutedor unsubstituted; R^(c) is H; and R^(d) is H.
 12. The method of claim11, wherein Aryl² is:

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a thioether group, a thioester group, athioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted; and R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,alkynyl, an alkoxy group, an ether group, a carboxylic acid group, acarboxaldehyde group, an ester group, an amine group, an amide group, acarbonate group, a carbamate group, a thioether group, a thioestergroup, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.
 13. The method of claim 12, wherein: R^(e)is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I,alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.
 14. The method of claim 12, wherein: R^(e)is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which issubstituted or unsubstituted; and R^(f) is alkyl, aryl, heterocyclyl, orheteroaryl, any of which is substituted or unsubstituted.
 15. The methodof claim 12, wherein: Aryl¹ is 4-phenylsulfamic acid; R^(a) is alkyl,which is substituted or unsubstituted; R^(b) is arylalkyl, which issubstituted or unsubstituted; R^(e) is H; and R^(f) is heteroaryl. 16.The method of claim 7, wherein the compound is:


17. The method of claim 7, wherein the compound is:


18. The method of claim 12, wherein: Aryl¹ is 4-phenylsulfamic acid;R^(a) is alkyl, which is substituted or unsubstituted; R^(b) isarylalkyl, which is substituted or unsubstituted; R^(e) is H; and R^(f)is alkyl.
 19. The method of claim 7, wherein the compound is:


20. The method of claim 7, wherein the compound is:


21. The method of claim 11, wherein Aryl² is:

wherein: R^(e) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, analkoxy group, an ether group, a carboxylic acid group, a carboxaldehydegroup, an ester group, an amine group, an amide group, a carbonategroup, a carbamate group, a thioether group, a thioester group, athioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is substituted orunsubstituted; and R^(f) is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,alkynyl, an alkoxy group, an ether group, a carboxylic acid group, acarboxaldehyde group, an ester group, an amine group, an amide group, acarbonate group, a carbamate group, a thioether group, a thioestergroup, a thioacid group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.
 22. The method of claim 21, wherein: R^(e)is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any ofwhich is substituted or unsubstituted; and R^(f) is H, OH, F, Cl, Br, I,alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which issubstituted or unsubstituted.
 23. The method of claim 21, wherein: R^(e)is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which issubstituted or unsubstituted; and R^(f) is alkyl, aryl, heterocyclyl, orheteroaryl, any of which is substituted or unsubstituted.
 24. The methodof claim 21, wherein: Aryl¹ is 4-phenylsulfamic acid; R^(a) is alkyl,which is substituted or unsubstituted; R^(b) is arylalkyl, which issubstituted or unsubstituted; R^(e) is H; and R^(f) is heteroaryl. 25.The method of claim 7, wherein the compound is:


26. The method of claim 7, wherein the compound is:


27. The method of claim 1, wherein the therapeutically-effective amountis from about 1 mg to about 100 mg.
 28. The method of claim 27, whereinthe therapeutically-effective amount is from about 0.5 mg to about 30mg.
 29. The method of claim 28, wherein the therapeutically-effectiveamount is about 15 mg.
 30. The method of claim 28, wherein thetherapeutically-effective amount is about 22.5 mg.
 31. The method ofclaim 1, wherein the therapeutically-effective amount is about 30 mg.32. The method of claim 1, wherein the administration is to an eye ofthe subject.
 33. The method of claim 1, wherein the administration isintravitreal.
 34. The method of claim 1, wherein the administration issubcutaneous.
 35. The method of claim 1, wherein the administration istopical.
 36. The method of claim 1, wherein the administration istopical to an eye of the subject.
 37. The method of claim 1, wherein theTie-2 activator, or a pharmaceutically-acceptable salt thereof, isformulated as a drop.
 38. The method of claim 1, wherein the Tie-2activator, or a pharmaceutically-acceptable salt thereof, is formulatedas a drop, wherein the drop is administered to an eye of the subject.39. The method of claim 1, wherein the subject is a human.
 40. Themethod of claim 1, wherein the intraocular pressure is reduced by atleast about 2 mmHg.
 41. The method of claim 1, wherein the subject hasglaucoma, wherein the intraocular pressure is associated with glaucoma.42. The method of claim 1, wherein the intraocular pressure is ocularhypertension.
 43. The method of claim 42, wherein the subject hasglaucoma, wherein the ocular hypertension is associated with glaucoma.44. A method for treating glaucoma in a subject in need thereof, themethod comprising administering to the subject atherapeutically-effective amount of a Tie-2 activator, wherein theadministration reduces intraocular pressure by about 0.1 mmHg to about 9mmHg compared to absence of administration.